Siegel, R. L., Giaquinto, A. N. & Jemal, A. Cancer statistics, 2024. CA Cancer J. Clin. 74, 12–49 (2024).
Google Scholar
Siegel, R. L. et al. Cancer statistics, 2025. CA Cancer J. Clin. 75, 10–45 (2025).
Google Scholar
Jin, F. et al. Recent advances in c-Met-based dual inhibitors in the treatment of cancers. Eur. J. Med. Chem. 272, 116477 (2024).
Google Scholar
Lee, Y. T., Tan, Y. J. & Oon, C. E. Molecular targeted therapy: treating cancer with specificity. Eur. J. Pharm. 834, 188–196 (2018).
Google Scholar
Mokdad, A. A., Hester, C. A., Singal, A. G. & Yopp, A. C. Management of hepatocellular in the United States. Chin. Clin. Oncol. 6, 21 (2017).
Google Scholar
Johnston, S. et al. Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy. J. Clin. Oncol. 26, 1066–1072 (2008).
Google Scholar
Belgioia, L. et al. Safety and efficacy of combined radiotherapy, immunotherapy and targeted agents in elderly patients: a literature review. Crit. Rev. Oncol. Hematol. 133, 163–170 (2019).
Google Scholar
Chow, L. Q. & Eckhardt, S. G. Sunitinib: from rational design to clinical efficacy. J. Clin. Oncol. 25, 884–896 (2007).
Google Scholar
Huh, C. G. et al. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc. Natl. Acad. Sci. USA 101, 4477–4482 (2004).
Google Scholar
Bladt, F. et al. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature 376, 768–771 (1995).
Google Scholar
Uehara, Y. et al. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature 373, 702–705 (1995).
Google Scholar
Schmidt, C. et al. Scatter factor/hepatocyte growth factor is essential for liver development. Nature 373, 699–702 (1995).
Google Scholar
Mitra, A. K. et al. Ligand-independent activation of c-Met by fibronectin and alpha(5)beta(1)-integrin regulates ovarian cancer invasion and metastasis. Oncogene 30, 1566–1576 (2011).
Google Scholar
Fujino, T. et al. Sensitivity and resistance of MET exon 14 mutations in lung cancer to eight MET tyrosine kinase inhibitors in vitro. J. Thorac. Oncol. 14, 1753–1765 (2019).
Google Scholar
Chen, E. C. et al. Targeting MET and FGFR in relapsed or refractory acute myeloid leukemia: preclinical and clinical findings, and signal transduction correlates. Clin. Cancer Res. 29, 878–887 (2023).
Google Scholar
Dhillon, S. Capmatinib: first approval. Drugs 80, 1125–1131 (2020).
Google Scholar
Brose, M. S. et al. Cabozantinib for previously treated radioiodine-refractory differentiated thyroid cancer: updated results from the phase 3 COSMIC-311 trial. Cancer 128, 4203–4212 (2022).
Google Scholar
Zarnegar, R. & Michalopoulos, G. Purification and biological characterization of human hepatopoietin A, a polypeptide growth factor for hepatocytes. Cancer Res. 49, 3314–3320 (1989).
Google Scholar
Thaler, F. J. & Michalopoulos, G. K. Hepatopoietin A: partial characterization and trypsin activation of a hepatocyte growth factor. Cancer Res. 45, 2545–2549 (1985).
Google Scholar
Nakamura, T. et al. Molecular cloning and expression of human hepatocyte growth factor. Nature 342, 440–443 (1989).
Google Scholar
Morell, R. J. et al. Noncoding microdeletion in mouse hgf disrupts neural crest migration into the stria vascularis, reduces the endocochlear potential, and suggests the neuropathology for human nonsyndromic deafness DFNB39. J. Neurosci. 40, 2976–2992 (2020).
Google Scholar
Rubin, J. S. et al. A broad-spectrum human lung fibroblast-derived mitogen is a variant of hepatocyte growth factor. Proc. Natl. Acad. Sci. USA 88, 415–419 (1991).
Google Scholar
Gille, J., Khalik, M., Konig, V. & Kaufmann, R. Hepatocyte growth factor/scatter factor (HGF/SF) induces vascular permeability factor (VPF/VEGF) expression by cultured keratinocytes. J. Invest. Dermatol. 111, 1160–1165 (1998).
Google Scholar
Weidner, K. M., Behrens, J., Vandekerckhove, J. & Birchmeier, W. Scatter factor: molecular characteristics and effect on the invasiveness of epithelial cells. J. Cell Biol. 111, 2097–2108 (1990).
Google Scholar
Schultz, J. M. et al. Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39. Am. J. Hum. Genet 85, 25–39 (2009).
Google Scholar
Van Der Steen, N. et al. cMET exon 14 skipping: from the structure to the clinic. J. Thorac. Oncol. 11, 1423–1432 (2016).
Google Scholar
Stoker, M., Gherardi, E., Perryman, M. & Gray, J. Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature 327, 239–242 (1987).
Google Scholar
Byeon, H. K., Ku, M. & Yang, J. Beyond EGFR inhibition: multilateral combat strategies to stop the progression of head and neck cancer. Exp. Mol. Med. 51, 1–14 (2019).
Google Scholar
Lokker, N. A. et al. Structure-function analysis of hepatocyte growth factor: identification of variants that lack mitogenic activity yet retain high affinity receptor binding. EMBO J. 11, 2503–2510 (1992).
Google Scholar
Holmes, O. et al. Insights into the structure/function of hepatocyte growth factor/scatter factor from studies with individual domains. J. Mol. Biol. 367, 395–408 (2007).
Google Scholar
Bottaro, D. P. et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251, 802–804 (1991).
Google Scholar
Cooper, C. S. et al. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 311, 29–33 (1984).
Google Scholar
Park, M. et al. Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc. Natl. Acad. Sci. USA 84, 6379–6383 (1987).
Google Scholar
Dean, M. et al. The human met oncogene is related to the tyrosine kinase oncogenes. Nature 318, 385–388 (1985).
Google Scholar
Komada, M. et al. Proteolytic processing of the hepatocyte growth factor/scatter factor receptor by furin. FEBS Lett. 328, 25–29 (1993).
Google Scholar
Organ, S. L. & Tsao, M. S. An overview of the c-MET signaling pathway. Ther. Adv. Med. Oncol. 3, S7–S19 (2011).
Google Scholar
Gherardi, E. et al. Functional map and domain structure of MET, the product of the c-met protooncogene and receptor for hepatocyte growth factor/scatter factor. Proc. Natl. Acad. Sci. USA 100, 12039–12044 (2003).
Google Scholar
Peschard, P. et al. Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. Mol. Cell 8, 995–1004 (2001).
Google Scholar
Rodrigues, G. A. & Park, M. Autophosphorylation modulates the kinase activity and oncogenic potential of the Met receptor tyrosine kinase. Oncogene 9, 2019–2027 (1994).
Google Scholar
Moosavi, F., Giovannetti, E., Saso, L. & Firuzi, O. HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers. Crit. Rev. Clin. Lab Sci. 56, 533–566 (2019).
Google Scholar
Fu, J. et al. HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence. Oncogene 40, 4625–4651 (2021).
Google Scholar
Venkatesh, S. & Workman, J. L. Histone exchange, chromatin structure and the regulation of transcription. Nat. Rev. Mol. Cell Biol. 16, 178–189 (2015).
Google Scholar
Zhang, J. & Babic, A. Regulation of the MET oncogene: molecular mechanisms. Carcinogenesis 37, 345–355 (2016).
Google Scholar
Du, J., Johnson, L. M., Jacobsen, S. E. & Patel, D. J. DNA methylation pathways and their crosstalk with histone methylation. Nat. Rev. Mol. Cell Biol. 16, 519–532 (2015).
Google Scholar
Nones, K. et al. Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling. Int. J. Cancer 135, 1110–1118 (2014).
Google Scholar
Marmorstein, R. & Zhou, M. M. Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb. Perspect. Biol. 6, a018762 (2014).
Google Scholar
Giordano, S. et al. Tyrosine kinase receptor indistinguishable from the c-met protein. Nature 339, 155–156 (1989).
Google Scholar
Gambarotta, G. et al. Structure and inducible regulation of the human MET promoter. J. Biol. Chem. 269, 12852–12857 (1994).
Google Scholar
Qian, J. et al. alpha2,6-hyposialylation of c-Met abolishes cell motility of ST6Gal-I-knockdown HCT116 cells. Acta Pharm. Sin. 30, 1039–1045 (2009).
Google Scholar
Wu, Y. M. et al. C1GALT1 enhances proliferation of hepatocellular carcinoma cells via modulating MET glycosylation and dimerization. Cancer Res. 73, 5580–5590 (2013).
Google Scholar
Chen, C. K. et al. Leukocyte cell-derived chemotaxin 2 antagonizes MET receptor activation to suppress hepatocellular carcinoma vascular invasion by protein tyrosine phosphatase 1B recruitment. Hepatology 59, 974–985 (2014).
Google Scholar
Giordano, S. et al. Biosynthesis of the protein encoded by the c-met proto-oncogene. Oncogene 4, 1383–1388 (1989).
Google Scholar
Navis, A. C. et al. Identification of a novel MET mutation in high-grade glioma resulting in an auto-active intracellular protein. Acta Neuropathol. 130, 131–144 (2015).
Google Scholar
Tiran, Z. et al. A novel recombinant soluble splice variant of Met is a potent antagonist of the hepatocyte growth factor/scatter factor-Met pathway. Clin. Cancer Res. 14, 4612–4621 (2008).
Google Scholar
Longati, P. et al. Tyrosines1234-1235 are critical for activation of the tyrosine kinase encoded by the MET proto-oncogene (HGF receptor). Oncogene 9, 49–57 (1994).
Google Scholar
Zhao, Y. et al. Lipopolysaccharide-induced phosphorylation of c-Met tyrosine residue 1003 regulates c-Met intracellular trafficking and lung epithelial barrier function. Am. J. Physiol. Lung Cell Mol. Physiol. 305, L56–L63 (2013).
Google Scholar
Fischer, O. M., Giordano, S., Comoglio, P. M. & Ullrich, A. Reactive oxygen species mediate Met receptor transactivation by G protein-coupled receptors and the epidermal growth factor receptor in human carcinoma cells. J. Biol. Chem. 279, 28970–28978 (2004).
Google Scholar
Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015).
Google Scholar
Jeffers, M. et al. Activating mutations for the met tyrosine kinase receptor in human cancer. Proc. Natl. Acad. Sci. USA 94, 11445–11450 (1997).
Google Scholar
Liu, X. et al. Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations. J. Clin. Oncol. 34, 794–802 (2016).
Google Scholar
Cioce, V. et al. Hepatocyte growth factor (HGF)/NK1 is a naturally occurring HGF/scatter factor variant with partial agonist/antagonist activity. J. Biol. Chem. 271, 13110–13115 (1996).
Google Scholar
Hartmann, G. et al. Engineered mutants of HGF/SF with reduced binding to heparan sulphate proteoglycans, decreased clearance and enhanced activity in vivo. Curr. Biol. 8, 125–134 (1998).
Google Scholar
Uchikawa, E. et al. Structural basis of the activation of c-MET receptor. Nat. Commun. 12, 4074 (2021).
Google Scholar
Huang, M. S. et al. LncRNAs and CircRNAs from the same gene: masterpieces of RNA splicing. Cancer Lett. 415, 49–57 (2018).
Google Scholar
Shan, C. et al. Biogenesis, functions and clinical significance of circRNAs in gastric cancer. Mol. Cancer 18, 136 (2019).
Google Scholar
Chen, L. L. The biogenesis and emerging roles of circular RNAs. Nat. Rev. Mol. Cell Biol. 17, 205–211 (2016).
Google Scholar
Bersani, F. et al. Exploring circular MET RNA as a potential biomarker in tumors exhibiting high MET activity. J. Exp. Clin. Cancer Res. 42, 120 (2023).
Google Scholar
Zhang, Y. et al. Circular intronic long noncoding RNAs. Mol. Cell 51, 792–806 (2013).
Google Scholar
Talhouarne, G. J. & Gall, J. G. Lariat intronic RNAs in the cytoplasm of Xenopus tropicalis oocytes. RNA 20, 1476–1487 (2014).
Google Scholar
Xu, H. et al. CircRNA_0000392 promotes colorectal cancer progression through the miR-193a-5p/PIK3R3/AKT axis. J. Exp. Clin. Cancer Res. 39, 283 (2020).
Google Scholar
Wang, L. et al. Estrogen-induced circRNA, circPGR, functions as a ceRNA to promote estrogen receptor-positive breast cancer cell growth by regulating cell cycle-related genes. Theranostics 11, 1732–1752 (2021).
Google Scholar
Dong, Z. et al. Identification of circRNA-miRNA-mRNA networks contributes to explore underlying pathogenesis and therapy strategy of gastric cancer. J. Transl. Med. 19, 226 (2021).
Google Scholar
Chen, L. & Shan, G. CircRNA in cancer: fundamental mechanism and clinical potential. Cancer Lett. 505, 49–57 (2021).
Google Scholar
Qiu, M. et al. The circular RNA circPRKCI promotes tumor growth in lung adenocarcinoma. Cancer Res. 78, 2839–2851 (2018).
Google Scholar
Kristensen, L. S., Hansen, T. B., Veno, M. T. & Kjems, J. Circular RNAs in cancer: opportunities and challenges in the field. Oncogene 37, 555–565 (2018).
Google Scholar
Yang, L. et al. CircMET promotes tumor proliferation by enhancing CDKN2A mRNA decay and upregulating SMAD3. Mol. Cancer 21, 23 (2022).
Google Scholar
Huang, X. Y. et al. Circular RNA circMET drives immunosuppression and anti-PD1 therapy resistance in hepatocellular carcinoma via the miR-30-5p/snail/DPP4 axis. Mol. Cancer 19, 92 (2020).
Google Scholar
Zhang, L. et al. The role of N(6)-methyladenosine (m(6)A) modification in the regulation of circRNAs. Mol. Cancer 19, 105 (2020).
Google Scholar
Dixit, D. et al. The RNA m6A reader YTHDF2 maintains oncogene expression and is a targetable dependency in glioblastoma stem cells. Cancer Discov. 11, 480–499 (2021).
Google Scholar
Yang, Y. et al. Extensive translation of circular RNAs driven by N(6)-methyladenosine. Cell Res. 27, 626–641 (2017).
Google Scholar
Liang, W. C. et al. Translation of the circular RNA circbeta-catenin promotes liver cancer cell growth through activation of the Wnt pathway. Genome Biol. 20, 84 (2019).
Google Scholar
Wu, X. et al. A novel protein encoded by circular SMO RNA is essential for Hedgehog signaling activation and glioblastoma tumorigenicity. Genome Biol. 22, 33 (2021).
Google Scholar
Gao, X. et al. Circular RNA-encoded oncogenic E-cadherin variant promotes glioblastoma tumorigenicity through activation of EGFR-STAT3 signalling. Nat. Cell Biol. 23, 278–291 (2021).
Google Scholar
Zhong, J. et al. Circular RNA encoded MET variant promotes glioblastoma tumorigenesis. Nat. Commun. 14, 4467 (2023).
Google Scholar
Bardelli, A. et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov. 3, 658–673 (2013).
Google Scholar
Gherardi, E. et al. Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc. Natl. Acad. Sci. USA 103, 4046–4051 (2006).
Google Scholar
Zhang, Y. W., Wang, L. M., Jove, R. & Vande Woude, G. F. Requirement of Stat3 signaling for HGF/SF-Met mediated tumorigenesis. Oncogene 21, 217–226 (2002).
Google Scholar
Pelicci, G. et al. The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein. Oncogene 10, 1631–1638 (1995).
Google Scholar
Salgia, R. MET in lung cancer: biomarker selection based on scientific rationale. Mol. Cancer Ther. 16, 555–565 (2017).
Google Scholar
Fan, S. et al. Role of NF-kappaB signaling in hepatocyte growth factor/scatter factor-mediated cell protection. Oncogene 24, 1749–1766 (2005).
Google Scholar
Giovannetti, E. et al. Never let it go: Stopping key mechanisms underlying metastasis to fight pancreatic cancer. Semin. Cancer Biol. 44, 43–59 (2017).
Google Scholar
Comoglio, P. M., Trusolino, L. & Boccaccio, C. Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy. Nat. Rev. Cancer 18, 341–358 (2018).
Google Scholar
Yamaoka, T. et al. Receptor tyrosine kinase-targeted cancer therapy. Int. J. Mol. Sci. 19, 3491 (2018).
Previdi, S. et al. Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and beta-catenin/Wnt pathways. Eur. J. Cancer 46, 1679–1691 (2010).
Google Scholar
Kim, K. H. et al. Wnt/beta-catenin signaling is a key downstream mediator of MET signaling in glioblastoma stem cells. Neuro Oncol. 15, 161–171 (2013).
Google Scholar
Tuynman, J. B. et al. Cyclooxygenase-2 inhibition inhibits c-Met kinase activity and Wnt activity in colon cancer. Cancer Res. 68, 1213–1220 (2008).
Google Scholar
Holland, J. D. et al. Combined Wnt/beta-catenin, Met, and CXCL12/CXCR4 signals characterize basal breast cancer and predict disease outcome. Cell Rep. 5, 1214–1227 (2013).
Google Scholar
Arend, R. C., Londono-Joshi, A. I., Straughn, J. M. Jr. & Buchsbaum, D. J. The Wnt/beta-catenin pathway in ovarian cancer: a review. Gynecol. Oncol. 131, 772–779 (2013).
Google Scholar
Liang, B. et al. Differential requirement of Hippo cascade during CTNNB1 or AXIN1 mutation-driven hepatocarcinogenesis. Hepatology 77, 1929–1942 (2023).
Google Scholar
Schaeper, U. et al. Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. J. Cell Biol. 149, 1419–1432 (2000).
Google Scholar
Lock, L. S., Royal, I., Naujokas, M. A. & Park, M. Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases. J. Biol. Chem. 275, 31536–31545 (2000).
Google Scholar
Maroun, C. R. et al. The Gab1 PH domain is required for localization of Gab1 at sites of cell-cell contact and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Mol. Cell Biol. 19, 1784–1799 (1999).
Google Scholar
Maroun, C. R. et al. The tyrosine phosphatase SHP-2 is required for sustained activation of extracellular signal-regulated kinase and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Mol. Cell Biol. 20, 8513–8525 (2000).
Google Scholar
Rahimi, N. et al. c-Src kinase activity is required for hepatocyte growth factor-induced motility and anchorage-independent growth of mammary carcinoma cells. J. Biol. Chem. 273, 33714–33721 (1998).
Google Scholar
Montagner, A. et al. A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation. J. Biol. Chem. 280, 5350–5360 (2005).
Google Scholar
Gual, P. et al. Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis. Oncogene 19, 1509–1518 (2000).
Google Scholar
Garcia-Guzman, M., Dolfi, F., Zeh, K. & Vuori, K. Met-induced JNK activation is mediated by the adapter protein Crk and correlates with the Gab1 – Crk signaling complex formation. Oncogene 18, 7775–7786 (1999).
Google Scholar
Weidner, K. M. et al. Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature 384, 173–176 (1996).
Google Scholar
Orian-Rousseau, V. et al. CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev. 16, 3074–3086 (2002).
Google Scholar
Conrotto, P. et al. Interplay between scatter factor receptors and B plexins controls invasive growth. Oncogene 23, 5131–5137 (2004).
Google Scholar
Giordano, S. et al. The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat. Cell Biol. 4, 720–724 (2002).
Google Scholar
Conrotto, P. et al. Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood 105, 4321–4329 (2005).
Google Scholar
Trusolino, L., Bertotti, A. & Comoglio, P. M. A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth. Cell 107, 643–654 (2001).
Google Scholar
Bertotti, A., Comoglio, P. M. & Trusolino, L. Beta4 integrin activates a Shp2-Src signaling pathway that sustains HGF-induced anchorage-independent growth. J. Cell Biol. 175, 993–1003 (2006).
Google Scholar
Wickramasinghe, D. & Kong-Beltran, M. Met activation and receptor dimerization in cancer: a role for the Sema domain. Cell Cycle 4, 683–685 (2005).
Google Scholar
Raj, S. et al. Molecular mechanism(s) of regulation(s) of c-MET/HGF signaling in head and neck cancer. Mol. Cancer 21, 31 (2022).
Google Scholar
Bradley, C. A. et al. Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges. Nat. Rev. Clin. Oncol. 14, 562–576 (2017).
Google Scholar
Bauer, T. W. et al. Regulatory role of c-Met in insulin-like growth factor-I receptor-mediated migration and invasion of human pancreatic carcinoma cells. Mol. Cancer Ther. 5, 1676–1682 (2006).
Google Scholar
Kissil, J. L. & Charest, A. New tools for dissecting RON receptor tyrosine kinase oncogenic signaling. Cancer Biol. Ther. 5, 1187–1188 (2006).
Google Scholar
Benvenuti, S. et al. Ron kinase transphosphorylation sustains MET oncogene addiction. Cancer Res. 71, 1945–1955 (2011).
Google Scholar
Tanizaki, J., Okamoto, I., Sakai, K. & Nakagawa, K. Differential roles of trans-phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification. Br. J. Cancer 105, 807–813 (2011).
Google Scholar
Heldin, C. H. Dimerization of cell surface receptors in signal transduction. Cell 80, 213–223 (1995).
Google Scholar
Shida, D. et al. Sphingosine 1-phosphate transactivates c-Met as well as epidermal growth factor receptor (EGFR) in human gastric cancer cells. FEBS Lett. 577, 333–338 (2004).
Google Scholar
Follenzi, A. et al. Cross-talk between the proto-oncogenes Met and Ron. Oncogene 19, 3041–3049 (2000).
Google Scholar
Li, W. et al. HGF-induced formation of the MET-AXL-ELMO2-DOCK180 complex promotes RAC1 activation, receptor clustering, and cancer cell migration and invasion. J. Biol. Chem. 293, 15397–15418 (2018).
Google Scholar
Salian-Mehta, S., Xu, M. & Wierman, M. E. AXL and MET crosstalk to promote gonadotropin releasing hormone (GnRH) neuronal cell migration and survival. Mol. Cell Endocrinol. 374, 92–100 (2013).
Google Scholar
Khoury, H. et al. HGF converts ErbB2/Neu epithelial morphogenesis to cell invasion. Mol. Biol. Cell 16, 550–561 (2005).
Google Scholar
Jo, M. et al. Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J. Biol. Chem. 275, 8806–8811 (2000).
Google Scholar
Dulak, A. M. et al. HGF-independent potentiation of EGFR action by c-Met. Oncogene 30, 3625–3635 (2011).
Google Scholar
Peinado, H. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18, 883–891 (2012).
Google Scholar
Dai, L. et al. Targeting HGF/c-MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma. Blood 126, 2821–2831 (2015).
Google Scholar
Di Renzo, M. F. et al. Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin. Cancer Res. 1, 147–154 (1995).
Google Scholar
Edakuni, G. et al. Expression of the hepatocyte growth factor/c-Met pathway is increased at the cancer front in breast carcinoma. Pathol. Int. 51, 172–178 (2001).
Google Scholar
Goyal, L., Muzumdar, M. D. & Zhu, A. X. Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin. Cancer Res. 19, 2310–2318 (2013).
Google Scholar
An, X. et al. MET amplification is not rare and predicts unfavorable clinical outcomes in patients with recurrent/metastatic gastric cancer after chemotherapy. Cancer 120, 675–682 (2014).
Google Scholar
Yeh, I. et al. Activating MET kinase rearrangements in melanoma and Spitz tumours. Nat. Commun. 6, 7174 (2015).
Google Scholar
Bao, Z. S. et al. RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas. Genome Res. 24, 1765–1773 (2014).
Google Scholar
International Cancer Genome Consortium PedBrain Tumor, P Recurrent MET fusion genes represent a drug target in pediatric glioblastoma. Nat. Med. 22, 1314–1320 (2016).
Google Scholar
Sun, D. et al. Identification of MET fusions as novel therapeutic targets sensitive to MET inhibitors in lung cancer. J. Transl. Med. 21, 150 (2023).
Google Scholar
Oliveres, H., Pineda, E. & Maurel, J. MET inhibitors in cancer: pitfalls and challenges. Expert Opin. Investig. Drugs 29, 73–85 (2020).
Google Scholar
Davies, K. D. et al. Dramatic response to crizotinib in a patient with lung cancer positive for an HLA-DRB1-MET gene fusion. JCO Precis. Oncol. 2017, PO.17.00117 (2017).
Guo, R. et al. MET-dependent solid tumours – molecular diagnosis and targeted therapy. Nat. Rev. Clin. Oncol. 17, 569–587 (2020).
Google Scholar
Gavine, P. R. et al. Volitinib, a potent and highly selective c-Met inhibitor, effectively blocks c-Met signaling and growth in c-MET amplified gastric cancer patient-derived tumor xenograft models. Mol. Oncol. 9, 323–333 (2015).
Google Scholar
Russo, A. L. et al. Urine analysis and protein networking identify met as a marker of metastatic prostate cancer. Clin. Cancer Res. 15, 4292–4298 (2009).
Google Scholar
Kentsis, A. et al. Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia. Nat. Med. 18, 1118–1122 (2012).
Google Scholar
Maroun, C. R. & Rowlands, T. The Met receptor tyrosine kinase: a key player in oncogenesis and drug resistance. Pharm. Ther. 142, 316–338 (2014).
Google Scholar
Daniel, S. K., Sullivan, K. M., Labadie, K. P. & Pillarisetty, V. G. Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma. Clin. Transl. Med. 8, 10 (2019).
Google Scholar
Pennacchietti, S. et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3, 347–361 (2003).
Google Scholar
Nault, J. C. et al. Clinical impact of genomic diversity from early to advanced hepatocellular carcinoma. Hepatology 71, 164–182 (2020).
Google Scholar
Harding, J. J. et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin. Cancer Res. 25, 2116–2126 (2019).
Google Scholar
Lee, S. J. et al. A survey of c-MET expression and amplification in 287 patients with hepatocellular carcinoma. Anticancer Res. 33, 5179–5186 (2013).
Google Scholar
Kondo, S. et al. Clinical impact of c-Met expression and its gene amplification in hepatocellular carcinoma. Int. J. Clin. Oncol. 18, 207–213 (2013).
Google Scholar
Wu, F. et al. The clinical value of hepatocyte growth factor and its receptor-c-met for liver cancer patients with hepatectomy. Dig. Liver Dis. 38, 490–497 (2006).
Google Scholar
Tavian, D. et al. u-PA and c-MET mRNA expression is co-ordinately enhanced while hepatocyte growth factor mRNA is down-regulated in human hepatocellular carcinoma. Int. J. Cancer 87, 644–649 (2000).
Google Scholar
Schoffski, P. et al. Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 ‘CREATE’. Ann. Oncol. 28, 3000–3008 (2017).
Google Scholar
Davis, I. J. et al. Identification of the receptor tyrosine kinase c-Met and its ligand, hepatocyte growth factor, as therapeutic targets in clear cell sarcoma. Cancer Res. 70, 639–645 (2010).
Google Scholar
Provencal, M. et al. c-Met activation in medulloblastoma induces tissue factor expression and activity: effects on cell migration. Carcinogenesis 30, 1089–1096 (2009).
Google Scholar
Sharma, R. & Malviya, R. Correlation between hypoxia and HGF/c-MET expression in the management of pancreatic cancer. Biochim. Biophys. Acta Rev. Cancer 1878, 188869 (2023).
Google Scholar
Zhang, Y. et al. The dual blockade of MET and VEGFR2 signaling demonstrates pronounced inhibition on tumor growth and metastasis of hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 37, 93 (2018).
Google Scholar
Dienstmann, R. et al. Molecular profiling of patients with colorectal cancer and matched targeted therapy in phase I clinical trials. Mol. Cancer Ther. 11, 2062–2071 (2012).
Google Scholar
Osada, S. et al. Effect of hepatocyte growth factor on progression of liver metastasis in colorectal cancer. Hepatogastroenterology 57, 76–80 (2010).
Google Scholar
Zeng, Z. S. et al. c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett. 265, 258–269 (2008).
Google Scholar
Yao, J. F. et al. Role of HGF/c-Met in the treatment of colorectal cancer with liver metastasis. J. Biochem. Mol. Toxicol. 33, e22316 (2019).
Google Scholar
Du, F. et al. SOX13 promotes colorectal cancer metastasis by transactivating SNAI2 and c-MET. Oncogene 39, 3522–3540 (2020).
Google Scholar
Luo, Y. et al. Long noncoding RNA GAPLINC promotes cells migration and invasion in colorectal cancer cell by regulating miR-34a/c-MET signal pathway. Dig. Dis. Sci. 63, 890–899 (2018).
Google Scholar
Shen, M. et al. Met is involved in TIGAR-regulated metastasis of non-small-cell lung cancer. Mol. Cancer 17, 88 (2018).
Google Scholar
Kajiya, K. et al. Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J. 24, 2885–2895 (2005).
Google Scholar
Nakamura, Y. et al. Constitutive activation of c-Met is correlated with c-Met overexpression and dependent on cell-matrix adhesion in lung adenocarcinoma cell lines. Cancer Sci. 99, 14–22 (2008).
Google Scholar
Roy, R., Yang, J. & Moses, M. A. Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J. Clin. Oncol. 27, 5287–5297 (2009).
Google Scholar
Cha, S. T. et al. MicroRNA-519c suppresses hypoxia-inducible factor-1alpha expression and tumor angiogenesis. Cancer Res. 70, 2675–2685 (2010).
Google Scholar
Michieli, P. et al. Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell 6, 61–73 (2004).
Google Scholar
Ding, S., Merkulova-Rainon, T., Han, Z. C. & Tobelem, G. HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro. Blood 101, 4816–4822 (2003).
Google Scholar
Qian, F. et al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res. 69, 8009–8016 (2009).
Google Scholar
Cascone, T. et al. The HGF/c-MET pathway is a driver and biomarker of VEGFR-inhibitor resistance and vascular remodeling in non-small cell lung cancer. Clin. Cancer Res. 23, 5489–5501 (2017).
Google Scholar
Xu, X. et al. c-Met and CREB1 are involved in miR-433-mediated inhibition of the epithelial-mesenchymal transition in bladder cancer by regulating Akt/GSK-3beta/Snail signaling. Cell Death Dis. 7, e2088 (2016).
Google Scholar
Sim, W. J. et al. c-Met activation leads to the establishment of a TGFbeta-receptor regulatory network in bladder cancer progression. Nat. Commun. 10, 4349 (2019).
Google Scholar
Van Schaeybroeck, S. et al. ADAM17-dependent c-MET-STAT3 signaling mediates resistance to MEK inhibitors in KRAS mutant colorectal cancer. Cell Rep. 7, 1940–1955 (2014).
Google Scholar
Zou, H. Y. et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 67, 4408–4417 (2007).
Google Scholar
Amemiya, H. et al. c-Met expression in gastric cancer with liver metastasis. Oncology 63, 286–296 (2002).
Google Scholar
Wu, X. et al. Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. Cancer Lett. 335, 128–135 (2013).
Google Scholar
Taniguchi, K. et al. The relation between the growth patterns of gastric carcinoma and the expression of hepatocyte growth factor receptor (c-met), autocrine motility factor receptor, and urokinase-type plasminogen activator receptor. Cancer 82, 2112–2122 (1998).
Google Scholar
Park, W. S. et al. Absence of mutations in the kinase domain of the Met gene and frequent expression of Met and HGF/SF protein in primary gastric carcinomas. APMIS 108, 195–200 (2000).
Google Scholar
Toiyama, Y. et al. Co-expression of hepatocyte growth factor and c-Met predicts peritoneal dissemination established by autocrine hepatocyte growth factor/c-Met signaling in gastric cancer. Int. J. Cancer 130, 2912–2921 (2012).
Google Scholar
Takeuchi, H. et al. c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. Clin. Cancer Res. 9, 1480–1488 (2003).
Google Scholar
Yi, Y. et al. Cancer-associated fibroblasts promote epithelial-mesenchymal transition and EGFR-TKI resistance of non-small cell lung cancers via HGF/IGF-1/ANXA2 signaling. Biochim Biophys. Acta Mol. Basis Dis. 1864, 793–803 (2018).
Google Scholar
Yano, S. et al. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res. 68, 9479–9487 (2008).
Google Scholar
Gayyed, M. F., Abd El-Maqsoud, N. M., El-Hameed El-Heeny, A. A. & Mohammed, M. F. c-MET expression in colorectal adenomas and primary carcinomas with its corresponding metastases. J. Gastrointest. Oncol. 6, 618–627 (2015).
Google Scholar
Sun, Y. L. et al. Expression of HGF and Met in human tissues of colorectal cancers: biological and clinical implications for synchronous liver metastasis. Int. J. Med. Sci. 10, 548–559 (2013).
Google Scholar
Jiang, W. G. et al. Regulation of spreading and growth of colon cancer cells by hepatocyte growth factor. Clin. Exp. Metastasis 11, 235–242 (1993).
Google Scholar
Oddo, D. et al. Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer. Br. J. Cancer 117, 347–352 (2017).
Google Scholar
Luraghi, P. et al. MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors. Cancer Res. 74, 1857–1869 (2014).
Google Scholar
Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).
Google Scholar
Yamaura, K. et al. Suppression of acute and chronic rejection by hepatocyte growth factor in a murine model of cardiac transplantation: induction of tolerance and prevention of cardiac allograft vasculopathy. Circulation 110, 1650–1657 (2004).
Google Scholar
Thompson, J. et al. HGF promotes survival and growth of maturing sympathetic neurons by PI-3 kinase- and MAP kinase-dependent mechanisms. Mol. Cell Neurosci. 27, 441–452 (2004).
Google Scholar
Shen, Z. et al. Molecular mechanism study of HGF/c-MET pathway activation and immune regulation for a tumor diagnosis model. Cancer Cell Int. 21, 374 (2021).
Google Scholar
Ilangumaran, S., Villalobos-Hernandez, A., Bobbala, D. & Ramanathan, S. The hepatocyte growth factor (HGF)-MET receptor tyrosine kinase signaling pathway: diverse roles in modulating immune cell functions. Cytokine 82, 125–139 (2016).
Google Scholar
Schag, K. et al. Identification of C-met oncogene as a broadly expressed tumor-associated antigen recognized by cytotoxic T-lymphocytes. Clin. Cancer Res. 10, 3658–3666 (2004).
Google Scholar
Fischer, K. et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812–3819 (2007).
Google Scholar
Glodde, N. et al. Reactive neutrophil responses dependent on the receptor tyrosine kinase c-MET limit cancer immunotherapy. Immunity 47, 789–802 e789, (2017).
Google Scholar
Lu, Z. et al. Mesenchymal stem cells induce dendritic cell immune tolerance via paracrine hepatocyte growth factor to alleviate acute lung injury. Stem Cell Res. Ther. 10, 372 (2019).
Google Scholar
Kurz, S. M. et al. The impact of c-met/scatter factor receptor on dendritic cell migration. Eur. J. Immunol. 32, 1832–1838 (2002).
Google Scholar
Singhal, E. & Sen, P. Hepatocyte growth factor-induced c-Src-phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway inhibits dendritic cell activation by blocking IkappaB kinase activity. Int. J. Biochem. Cell Biol. 43, 1134–1146 (2011).
Google Scholar
Singhal, E., Kumar, P. & Sen, P. A novel role for Bruton’s tyrosine kinase in hepatocyte growth factor-mediated immunoregulation of dendritic cells. J. Biol. Chem. 286, 32054–32063 (2011).
Google Scholar
Rutella, S. et al. Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10 + + IL-12low/neg accessory cells with dendritic-cell features. Blood 108, 218–227 (2006).
Google Scholar
Baek, J. H., Birchmeier, C., Zenke, M. & Hieronymus, T. The HGF receptor/Met tyrosine kinase is a key regulator of dendritic cell migration in skin immunity. J. Immunol. 189, 1699–1707 (2012).
Google Scholar
Benkhoucha, M. et al. Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25+Foxp3+ regulatory T cells. Proc. Natl. Acad. Sci. USA 107, 6424–6429 (2010).
Google Scholar
Yue, F. Y. et al. Interleukin-10 is a growth factor for human melanoma cells and down-regulates HLA class-I, HLA class-II and ICAM-1 molecules. Int. J. Cancer 71, 630–637 (1997).
Google Scholar
Ludewig, B. et al. Spontaneous apoptosis of dendritic cells is efficiently inhibited by TRAP (CD40-ligand) and TNF-alpha, but strongly enhanced by interleukin-10. Eur. J. Immunol. 25, 1943–1950 (1995).
Google Scholar
Jing, W. et al. Tumor-neutrophil cross talk orchestrates the tumor microenvironment to determine the bladder cancer progression. Proc. Natl. Acad. Sci. USA 121, e2312855121 (2024).
Google Scholar
Finisguerra, V. et al. MET is required for the recruitment of anti-tumoural neutrophils. Nature 522, 349–353 (2015).
Google Scholar
Yao, S. et al. Unveiling the role of HGF/c-Met signaling in non-small cell lung cancer tumor microenvironment. Int. J. Mol. Sci. 25, 9101 (2024).
Chen, P. M. et al. Induction of immunomodulatory monocytes by human mesenchymal stem cell-derived hepatocyte growth factor through ERK1/2. J. Leukoc. Biol. 96, 295–303 (2014).
Google Scholar
Fehrenbacher, L. et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387, 1837–1846 (2016).
Google Scholar
Sun, Y. et al. PD-L1(+) exosomes from bone marrow-derived cells of tumor-bearing mice inhibit antitumor immunity. Cell Mol. Immunol. 18, 2402–2409 (2021).
Google Scholar
Ahn, H. K. et al. MET receptor tyrosine kinase regulates the expression of co-stimulatory and co-inhibitory molecules in tumor cells and contributes to PD-L1-mediated suppression of immune cell function. Int. J. Mol. Sci. 20, 4287 (2019).
Saigi, M. et al. MET-oncogenic and JAK2-inactivating alterations are independent factors that affect regulation of PD-L1 expression in lung cancer. Clin. Cancer Res. 24, 4579–4587 (2018).
Google Scholar
Yoshida, R. et al. MET-induced CD73 restrains STING-mediated immunogenicity of EGFR-mutant lung cancer. Cancer Res. 82, 4079–4092 (2022).
Google Scholar
Li, E., Huang, X., Zhang, G. & Liang, T. Combinational blockade of MET and PD-L1 improves pancreatic cancer immunotherapeutic efficacy. J. Exp. Clin. Cancer Res. 40, 279 (2021).
Google Scholar
Balan, M. et al. Novel roles of c-Met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression. J. Biol. Chem. 290, 8110–8120 (2015).
Google Scholar
Xu, R. et al. c-Met up-regulates the expression of PD-L1 through MAPK/NF-kappaBp65 pathway. J. Mol. Med. 100, 585–598 (2022).
Google Scholar
Peng, S. et al. EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression. Mol. Cancer 18, 165 (2019).
Google Scholar
Wang, Q. W. et al. MET overexpression contributes to STAT4-PD-L1 signaling activation associated with tumor-associated, macrophages-mediated immunosuppression in primary glioblastomas. J. Immunother. Cancer 9, e002451 (2021).
Galli, R. et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64, 7011–7021 (2004).
Google Scholar
Collins, A. T. et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65, 10946–10951 (2005).
Google Scholar
Al-Hajj, M. et al. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 100, 3983–3988 (2003).
Google Scholar
O’Brien, C. A., Pollett, A., Gallinger, S. & Dick, J. E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110 (2007).
Google Scholar
Li, Y. et al. c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc. Natl. Acad. Sci. USA 108, 9951–9956 (2011).
Google Scholar
Huang, W. C. et al. IFI44L is a novel tumor suppressor in human hepatocellular carcinoma affecting cancer stemness, metastasis, and drug resistance via regulating met/Src signaling pathway. BMC Cancer 18, 609 (2018).
Google Scholar
Jeon, H. M. & Lee, J. MET: roles in epithelial-mesenchymal transition and cancer stemness. Ann. Transl. Med. 5, 5 (2017).
Google Scholar
Saygin, C. et al. Targeting cancer stemness in the clinic: from hype to hope. Cell Stem Cell 24, 25–40 (2019).
Google Scholar
Nassar, D. & Blanpain, C. Cancer stem cells: basic concepts and therapeutic implications. Annu. Rev. Pathol. 11, 47–76 (2016).
Google Scholar
Andermarcher, E., Surani, M. A. & Gherardi, E. Co-expression of the HGF/SF and c-met genes during early mouse embryogenesis precedes reciprocal expression in adjacent tissues during organogenesis. Dev. Genet. 18, 254–266 (1996).
Google Scholar
Latimer, A. J. & Jessen, J. R. Hgf/c-met expression and functional analysis during zebrafish embryogenesis. Dev. Dyn. 237, 3904–3915 (2008).
Google Scholar
Rath, P. et al. In vivo c-Met pathway inhibition depletes human glioma xenografts of tumor-propagating stem-like cells. Transl. Oncol. 6, 104–111 (2013).
Google Scholar
Joo, K. M. et al. MET signaling regulates glioblastoma stem cells. Cancer Res. 72, 3828–3838 (2012).
Google Scholar
Flores-Tellez, T. N., Villa-Trevino, S. & Pina-Vazquez, C. Road to stemness in hepatocellular carcinoma. World J. Gastroenterol. 23, 6750–6776 (2017).
Google Scholar
Sun, S. et al. Targeting the c-Met/FZD8 signaling axis eliminates patient-derived cancer stem-like cells in head and neck squamous carcinomas. Cancer Res. 74, 7546–7559 (2014).
Google Scholar
Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 12, 468–476 (2010).
Google Scholar
MacDonald, B. T., Tamai, K. & He, X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17, 9–26 (2009).
Google Scholar
Arnold, L., Enders, J. & Thomas, S. M. Activated HGF-c-met axis in head and neck cancer. Cancers. 9, 169 (2017).
Xing, F. et al. Activation of the c-met pathway mobilizes an inflammatory network in the brain microenvironment to promote brain metastasis of breast cancer. Cancer Res. 76, 4970–4980 (2016).
Google Scholar
Li, Y. et al. The scatter factor/hepatocyte growth factor: c-met pathway in human embryonal central nervous system tumor malignancy. Cancer Res. 65, 9355–9362 (2005).
Google Scholar
Yan, B. et al. Paracrine HGF/c-MET enhances the stem cell-like potential and glycolysis of pancreatic cancer cells via activation of YAP/HIF-1alpha. Exp. Cell Res. 371, 63–71 (2018).
Google Scholar
Lau, E. Y. et al. Cancer-associated fibroblasts regulate tumor-initiating cell plasticity in hepatocellular carcinoma through c-Met/FRA1/HEY1 signaling. Cell Rep. 15, 1175–1189 (2016).
Google Scholar
Essex, A. et al. Replication study: Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Elife. 8, e45426 (2019).
Evans, J. et al. Registered report: Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Elife. 4, e05417 (2015).
Koike, H. et al. Macrophage subpopulation promotes skeletal muscle regeneration through HGF/MET signaling-mediated skeletal muscle stem cell proliferation. Aging Cell e70042 (2025).
Hu, L. et al. Leveraging CAR macrophages targeting c-Met for precision immunotherapy in pancreatic cancer: insights from single-cell multi-omics. Mol. Med. 30, 231 (2024).
Google Scholar
Huang, X. et al. The HGF-MET axis coordinates liver cancer metabolism and autophagy for chemotherapeutic resistance. Autophagy 15, 1258–1279 (2019).
Google Scholar
Jahangiri, A. et al. Cross-activating c-Met/beta1 integrin complex drives metastasis and invasive resistance in cancer. Proc. Natl. Acad. Sci. USA 114, E8685–E8694 (2017).
Google Scholar
Westover, D. et al. Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann. Oncol. 29, i10–i19 (2018).
Google Scholar
Wu, Y. L. et al. Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial. Lancet Respir. Med. 8, 1132–1143 (2020).
Google Scholar
Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).
Google Scholar
Bean, J. et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl. Acad. Sci. USA 104, 20932–20937 (2007).
Google Scholar
Liu, N. et al. Reversing MET-mediated resistance in oncogene-driven NSCLC by MET-activated Wnt condensative prodrug. Adv. Sci. 11, e2400603 (2024).
Google Scholar
Huang, M. et al. Wnt-mediated endothelial transformation into mesenchymal stem cell-like cells induces chemoresistance in glioblastoma. Sci Transl Med. 12, eaay7522 (2020).
Rosell, R., Chaib, I. & Santarpia, M. Targeting MET amplification in EGFR-mutant non-small-cell lung cancer. Lancet Respir. Med. 8, 1068–1070 (2020).
Google Scholar
Aebersold, D. M. et al. Prevalence and clinical impact of Met Y1253D-activating point mutation in radiotherapy-treated squamous cell cancer of the oropharynx. Oncogene 22, 8519–8523 (2003).
Google Scholar
Wang, B. et al. Cancer-associated fibroblasts promote radioresistance of breast cancer cells via the HGF/c-Met signaling pathway. Int. J. Radiat. Oncol. Biol. Phys. 116, 640–654 (2023).
Google Scholar
Jankowski, K. et al. Both hepatocyte growth factor (HGF) and stromal-derived factor-1 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only HGF enhances their resistance to radiochemotherapy. Cancer Res. 63, 7926–7935 (2003).
Google Scholar
Pyo, J. S., Kang, G., Cho, W. J. & Choi, S. B. Clinicopathological significance and concordance analysis of c-MET immunohistochemistry in non-small cell lung cancers: a meta-analysis. Pathol. Res. Pract. 212, 710–716 (2016).
Google Scholar
Awad, M. M. et al. MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-met overexpression. J. Clin. Oncol. 34, 721–730 (2016).
Google Scholar
Song, Z. et al. De novo MET amplification in chinese patients with non-small-cell lung cancer and treatment efficacy with crizotinib: a multicenter retrospective study. Clin. Lung Cancer 20, e171–e176 (2019).
Google Scholar
Vuong, H. G. et al. Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer – a systematic review and meta-analysis. Lung Cancer 123, 76–82 (2018).
Google Scholar
Kim, J. H., Kim, H. S. & Kim, B. J. Prognostic value of MET copy number gain in non-small-cell lung cancer: an updated meta-analysis. J. Cancer 9, 1836–1845 (2018).
Google Scholar
Fois, S. S. et al. Molecular epidemiology of the main druggable genetic alterations in non-small cell lung cancer. Int. J. Mol. Sci. 22, 612 (2021).
Spitaleri, G. et al. MET in non-small-cell lung cancer (NSCLC): cross ‘a long and winding road’ looking for a target. Cancers 15, 4779 (2023).
Zagouri, F. et al. High MET expression is an adverse prognostic factor in patients with triple-negative breast cancer. Br. J. Cancer 108, 1100–1105 (2013).
Google Scholar
Yan, S., Jiao, X., Zou, H. & Li, K. Prognostic significance of c-Met in breast cancer: a meta-analysis of 6010 cases. Diagn. Pathol. 10, 62 (2015).
Google Scholar
Ho-Yen, C. M., Jones, J. L. & Kermorgant, S. The clinical and functional significance of c-Met in breast cancer: a review. Breast Cancer Res. 17, 52 (2015).
Google Scholar
Wang, F. et al. Predictive role of the overexpression for CXCR4, C-Met, and VEGF-C among breast cancer patients: a meta-analysis. Breast 28, 45–53 (2016).
Google Scholar
Resnick, M. B. et al. Epidermal growth factor receptor, c-MET, beta-catenin, and p53 expression as prognostic indicators in stage II colon cancer: a tissue microarray study. Clin. Cancer Res. 10, 3069–3075 (2004).
Google Scholar
Ginty, F. et al. The relative distribution of membranous and cytoplasmic met is a prognostic indicator in stage I and II colon cancer. Clin. Cancer Res. 14, 3814–3822 (2008).
Google Scholar
Lee, C. T. et al. The prognostic significance of RON and MET receptor coexpression in patients with colorectal cancer. Dis. Colon Rectum 51, 1268–1274 (2008).
Google Scholar
De Oliveira, A. T. et al. MET is highly expressed in advanced stages of colorectal cancer and indicates worse prognosis and mortality. Anticancer Res. 29, 4807–4811 (2009).
Google Scholar
Liu, Y., Yu, X. F., Zou, J. & Luo, Z. H. Prognostic value of c-Met in colorectal cancer: a meta-analysis. World J. Gastroenterol. 21, 3706–3710 (2015).
Google Scholar
Lee, S. J. et al. c-MET overexpression in colorectal cancer: a poor prognostic factor for survival. Clin. Colorectal Cancer 17, 165–169 (2018).
Google Scholar
Huang, K. H. et al. Correlation between HGF/c-Met and Notch1 signaling pathways in human gastric cancer cells. Oncol. Rep. 40, 294–302 (2018).
Google Scholar
Choi, J. et al. Evaluation of intratumoral and intertumoral heterogeneity of MET protein expression in gastric cancer. Appl. Immunohistochem. Mol. Morphol. 26, 445–453 (2018).
Google Scholar
Catenacci, D. V. et al. MET tyrosine kinase receptor expression and amplification as prognostic biomarkers of survival in gastroesophageal adenocarcinoma. Cancer 123, 1061–1070 (2017).
Google Scholar
Ren, J. L. et al. C-Met as a potential novel prognostic marker in squamous cell carcinoma and adenocarcinoma of esophagus: evidence from a meta-analysis. Panminerva Med. 59, 97–106 (2017).
Google Scholar
Szturz, P. et al. Prognostic value of c-MET in head and neck cancer: a systematic review and meta-analysis of aggregate data. Oral. Oncol. 74, 68–76 (2017).
Google Scholar
Vsiansky, V., Gumulec, J., Raudenska, M. & Masarik, M. Prognostic role of c-Met in head and neck squamous cell cancer tissues: a meta-analysis. Sci. Rep. 8, 10370 (2018).
Google Scholar
Rimassa, L. et al. Outcomes based on plasma biomarkers for the phase 3 celestial trial of cabozantinib versus placebo in advanced hepatocellular carcinoma. Liver Cancer 11, 38–47 (2022).
Google Scholar
Yu, J., Chen, G. G. & Lai, P. B. S. Targeting hepatocyte growth factor/c-mesenchymal-epithelial transition factor axis in hepatocellular carcinoma: Rationale and therapeutic strategies. Med. Res. Rev. 41, 507–524 (2021).
Google Scholar
Gibney, G. T. et al. c-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma. Ann. Oncol. 24, 343–349 (2013).
Google Scholar
Tsai, H. W. et al. The significance of prohibitin and c-Met/hepatocyte growth factor receptor in the progression of cervical adenocarcinoma. Hum. Pathol. 37, 198–204 (2006).
Google Scholar
Peng, J. et al. Diagnosis and prognostic significance of c-Met in cervical cancer: a meta-analysis. Dis. Markers 2016, 6594016 (2016).
Google Scholar
Boromand, N. et al. Clinical and prognostic value of the C-Met/HGF signaling pathway in cervical cancer. J. Cell Physiol. 233, 4490–4496 (2018).
Google Scholar
Fuse, N. et al. Prognostic impact of HER2, EGFR, and c-MET status on overall survival of advanced gastric cancer patients. Gastric Cancer 19, 183–191 (2016).
Google Scholar
Xu, Y. et al. Expression and clinical significance of c-Met in advanced esophageal squamous cell carcinoma. BMC Cancer 15, 6 (2015).
Google Scholar
Lee, H. E. et al. MET in gastric carcinomas: comparison between protein expression and gene copy number and impact on clinical outcome. Br. J. Cancer 107, 325–333 (2012).
Google Scholar
Remon, J. et al. MET alterations in NSCLC-current perspectives and future challenges. J. Thorac. Oncol. 18, 419–435 (2023).
Google Scholar
Spagnolo, C. C. et al. Targeting MET in non-small cell lung cancer (NSCLC): a new old story? Int. J. Mol. Sci. 24, 10119 (2023).
Zhang, Y., Shen, L. & Peng, Z. Advances in MET tyrosine kinase inhibitors in gastric cancer. Cancer Biol. Med. 21, 484–498 (2024).
Google Scholar
Jin, Y. et al. The predicting role of circulating tumor DNA landscape in gastric cancer patients treated with immune checkpoint inhibitors. Mol. Cancer 19, 154 (2020).
Google Scholar
Voutsina, A. et al. Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer. Mod. Pathol. 26, 302–313 (2013).
Google Scholar
Al-Maghrabi, J. et al. c-MET immunostaining in colorectal carcinoma is associated with local disease recurrence. BMC Cancer 15, 676 (2015).
Google Scholar
Wan, X., Li, Z. & Zhou, L. c-MET is an important marker for acid-driven metastasis and anti-immune in colorectal cancer. Int Immunopharmacol. 142, 113153 (2024).
Google Scholar
Schweiger, T. et al. Clinical impact of c-MET expression and mutational status in patients with colorectal cancer lung metastases. Eur. J. Cardiothorac. Surg. 49, 1103–1111 (2016).
Google Scholar
Mo, H. N. & Liu, P. Targeting MET in cancer therapy. Chronic Dis. Transl. Med. 3, 148–153 (2017).
Google Scholar
Roskoski, R. Jr. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharm. Res. 103, 26–48 (2016).
Google Scholar
Kim, K. H. & Kim, H. Progress of antibody-based inhibitors of the HGF-cMET axis in cancer therapy. Exp. Mol. Med. 49, e307 (2017).
Google Scholar
Zhu, Z. et al. Membrane-bounded intracellular E3 ubiquitin ligase-targeting chimeras (MembTACs) for targeted membrane protein degradation. Angew. Chem. Int. Ed. Engl. e202501857, (2025).
Fu, X. et al. Development of dual aptamers-functionalized c-MET PROTAC degraders for targeted therapy of osteosarcoma. Theranostics 15, 103–121 (2025).
Google Scholar
Dai, Y., Bae, K., Pampo, C. & Siemann, D. W. Impact of the small molecule Met inhibitor BMS-777607 on the metastatic process in a rodent tumor model with constitutive c-Met activation. Clin. Exp. Metastasis 29, 253–261 (2012).
Google Scholar
Nan, X. et al. Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction. Eur. J. Med. Chem. 200, 112470 (2020).
Google Scholar
Parikh, P. K. & Ghate, M. D. Recent advances in the discovery of small molecule c-Met Kinase inhibitors. Eur. J. Med. Chem. 143, 1103–1138 (2018).
Google Scholar
Li, M. J. et al. Development of efficient docking strategies and structure-activity relationship study of the c-Met type II inhibitors. J. Mol. Graph Model 75, 241–249 (2017).
Google Scholar
El-Wakil, M. H. & Teleb, M. Transforming type II to type I c-Met kinase inhibitors via combined scaffold hopping and structure-guided synthesis of new series of 1,3,4-thiadiazolo[2,3-c]-1,2,4-triazin-4-one derivatives. Bioorg. Chem. 116, 105304 (2021).
Google Scholar
Nan, X. et al. Design, synthesis and evaluation of sulfonylurea-containing 4-phenoxyquinolines as highly selective c-Met kinase inhibitors. Bioorg. Med. Chem. 27, 2801–2812 (2019).
Google Scholar
Baljevic, M. et al. Phase II study of the c-MET inhibitor tivantinib (ARQ 197) in patients with relapsed or relapsed/refractory multiple myeloma. Ann. Hematol. 96, 977–985 (2017).
Google Scholar
Pan, B. S. et al. MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 70, 1524–1533 (2010).
Google Scholar
Rota Caremoli, E. & Labianca, R. Tivantinib: critical review with a focus on hepatocellular carcinoma. Expert Opin. Investig. Drugs 23, 1563–1574 (2014).
Google Scholar
Chu, C., Rao, Z., Pan, Q. & Zhu, W. An updated patent review of small-molecule c-Met kinase inhibitors (2018-present). Expert Opin. Ther. Pat. 32, 279–298 (2022).
Google Scholar
Cui, J. J. et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J. Med. Chem. 54, 6342–6363 (2011).
Google Scholar
Puccini, A. et al. Safety and tolerability of c-MET inhibitors in cancer. Drug Saf. 42, 211–233 (2019).
Google Scholar
Drilon, A. et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat. Med. 26, 47–51 (2020).
Google Scholar
Moro-Sibilot, D. et al. Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSe phase II trial. Ann. Oncol. 30, 1985–1991 (2019).
Google Scholar
Camidge, D. R. et al. Crizotinib in patients with MET-amplified NSCLC. J. Thorac. Oncol. 16, 1017–1029 (2021).
Google Scholar
Schoffski, P. et al. Crizotinib achieves long-lasting disease control in advanced papillary renal-cell carcinoma type 1 patients with MET mutations or amplification. EORTC 90101 CREATE trial. Eur. J. Cancer 87, 147–163 (2017).
Google Scholar
Liu, X. et al. A novel kinase inhibitor, INCB28060, blocks c-MET-dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3. Clin. Cancer Res. 17, 7127–7138 (2011).
Google Scholar
Mori, S. et al. Inhibition of c-MET reverses radiation-induced malignant potential in pancreatic cancer. Cancer Lett. 512, 51–59 (2021).
Google Scholar
Bang, Y. J. et al. Phase 1 study of capmatinib in MET-positive solid tumor patients: dose escalation and expansion of selected cohorts. Cancer Sci. 111, 536–547 (2020).
Google Scholar
Baltschukat, S. et al. Capmatinib (INC280) is active against models of non-small cell lung cancer and other cancer types with defined mechanisms of MET activation. Clin. Cancer Res. 25, 3164–3175 (2019).
Google Scholar
Wu, Y. L. et al. Phase Ib/II study of capmatinib (INC280) plus gefitinib after failure of epidermal growth factor receptor (EGFR) inhibitor therapy in patients with EGFR-mutated, MET factor-dysregulated non-small-cell lung cancer. J. Clin. Oncol. 36, 3101–3109 (2018).
Google Scholar
Wolf, J. et al. Capmatinib in MET Exon 14-mutated or MET-amplified non-small-cell lung cancer. N. Engl. J. Med. 383, 944–957 (2020).
Google Scholar
Schuler, M. et al. Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial. Ann. Oncol. 31, 789–797 (2020).
Google Scholar
Hsu, R., Benjamin, D. J. & Nagasaka, M. The development and role of capmatinib in the treatment of MET-dysregulated non-small cell lung cancer—a narrative review. Cancers 15, 3561 (2023).
Dagogo-Jack, I. et al. A phase 2 study of capmatinib in patients with MET-altered lung cancer previously treated with a MET inhibitor. J. Thorac. Oncol. 16, 850–859 (2021).
Google Scholar
Wang, K. et al. Brief report: clinical response, toxicity, and resistance mechanisms to osimertinib plus MET inhibitors in patients with EGFR-mutant MET-amplified NSCLC. JTO Clin. Res. Rep. 4, 100533 (2023).
Google Scholar
Wolf, J. et al. Capmatinib in MET exon 14-mutated non-small-cell lung cancer: final results from the open-label, phase 2 GEOMETRY mono-1 trial. Lancet Oncol. 25, 1357–1370 (2024).
Google Scholar
Jia, H. et al. Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (volitinib) as a highly potent and selective mesenchymal-epithelial transition factor (c-Met) inhibitor in clinical development for treatment of cancer. J. Med. Chem. 57, 7577–7589 (2014).
Google Scholar
Sequist, L. V. et al. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study. Lancet Oncol. 21, 373–386 (2020).
Google Scholar
Yang, J. J. et al. A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer. Invest. New Drugs 39, 477–487 (2021).
Google Scholar
Lu, S. et al. Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study. Lancet Respir. Med. 9, 1154–1164 (2021).
Google Scholar
Choueiri, T. K. et al. Efficacy of savolitinib vs sunitinib in patients with MET-driven papillary renal cell carcinoma: the SAVOIR phase 3 randomized clinical trial. JAMA Oncol. 6, 1247–1255 (2020).
Google Scholar
Choueiri, T. K. et al. Biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer. J. Clin. Oncol. 35, 2993–3001 (2017).
Google Scholar
Dantas-Barbosa, C. et al. Expression and role of TYRO3 and AXL as potential therapeutical targets in leiomyosarcoma. Br. J. Cancer 117, 1787–1797 (2017).
Google Scholar
Rayson, D. et al. Canadian Cancer Trials Group IND197: a phase II study of foretinib in patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative recurrent or metastatic breast cancer. Breast Cancer Res. Treat. 157, 109–116 (2016).
Google Scholar
Eder, J. P. et al. A phase I study of foretinib, a multi-targeted inhibitor of c-Met and vascular endothelial growth factor receptor 2. Clin. Cancer Res. 16, 3507–3516 (2010).
Google Scholar
Yau, T. C. C. et al. A phase I/II multicenter study of single-agent foretinib as first-line therapy in patients with advanced hepatocellular carcinoma. Clin. Cancer Res. 23, 2405–2413 (2017).
Google Scholar
Choueiri, T. K. et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J. Clin. Oncol. 31, 181–186 (2013).
Google Scholar
Bladt, F. et al. EMD 1214063 and EMD 1204831 constitute a new class of potent and highly selective c-Met inhibitors. Clin. Cancer Res. 19, 2941–2951 (2013).
Google Scholar
You, H. et al. c-Met represents a potential therapeutic target for personalized treatment in hepatocellular carcinoma. Hepatology 54, 879–889 (2011).
Google Scholar
Bladt, F. et al. The c-Met inhibitor MSC2156119J effectively inhibits tumor growth in liver cancer models. Cancers 6, 1736–1752 (2014).
Google Scholar
Falchook, G. S. et al. First-in-man phase I trial of the selective MET inhibitor tepotinib in patients with advanced solid tumors. Clin. Cancer Res. 26, 1237–1246 (2020).
Google Scholar
Decaens, T. et al. Phase 1b/2 trial of tepotinib in sorafenib pretreated advanced hepatocellular carcinoma with MET overexpression. Br. J. Cancer 125, 190–199 (2021).
Google Scholar
Paik, P. K. et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N. Engl. J. Med. 383, 931–943 (2020).
Google Scholar
Ryoo, B. Y. et al. Randomised Phase 1b/2 trial of tepotinib vs sorafenib in Asian patients with advanced hepatocellular carcinoma with MET overexpression. Br. J. Cancer 125, 200–208 (2021).
Google Scholar
Wu, Y. L. et al. Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial. Lancet Oncol. 25, 989–1002 (2024).
Google Scholar
Mazieres, J. et al. Tepotinib treatment in patients with MET exon 14-skipping non-small cell lung cancer: long-term follow-up of the VISION phase 2 nonrandomized clinical trial. JAMA Oncol. 9, 1260–1266 (2023).
Google Scholar
Cui, X. et al. Simultaneous determination of a novel c-Met/AXL dual-target small-molecule inhibitor BPI-9016M and its metabolites in human plasma by liquid chromatography-tandem mass spectrometry: Application in a pharmacokinetic study in Chinese advanced solid tumor patients. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 1068-1069, 33–40 (2017).
Google Scholar
Zhang, P. et al. BPI-9016M, a c-Met inhibitor, suppresses tumor cell growth, migration and invasion of lung adenocarcinoma via miR203-DKK1. Theranostics 8, 5890–5902 (2018).
Google Scholar
Hu, X. et al. First-in-human phase I study of BPI-9016M, a dual MET/Axl inhibitor, in patients with non-small cell lung cancer. J. Hematol. Oncol. 13, 6 (2020).
Google Scholar
Christensen, J. G. et al. A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res. 63, 7345–7355 (2003).
Google Scholar
Yadav, A. K., Wang, S., Shin, Y. M. & Jang, B. C. PHA-665752’s antigrowth and proapoptotic effects on HSC-3 human oral cancer cells. Int. J. Mol. Sci. 25, 2871 (2024).
Smolen, G. A. et al. Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc. Natl. Acad. Sci. USA 103, 2316–2321 (2006).
Google Scholar
Jia, Y. T. et al. Effects of PHA-665752 and cetuximab combination treatment on in vitro and murine xenograft growth of human colorectal cancer cells with KRAS or BRAF mutations. Curr. Cancer Drug Targets 18, 278–286 (2018).
Google Scholar
Kim, N. A. et al. New preclinical development of a c-Met inhibitor and its combined anti-tumor effect in c-met-amplified NSCLC. Pharmaceutics. 12, 121 (2020).
Ravi, M. et al. Solubility determination of c-Met inhibitor in solvent mixtures and mathematical modeling to develop nanosuspension formulation. Molecules. 26, 390 (2021).
Sahi, J., Khan, K. K. & Black, C. B. Aldehyde oxidase activity and inhibition in hepatocytes and cytosolic fractions from mouse, rat, monkey and human. Drug Metab. Lett. 2, 176–183 (2008).
Google Scholar
Kim, J. et al. Therapeutic efficacy of ABN401, a highly potent and selective MET inhibitor, based on diagnostic biomarker test in MET-addicted cancer. Cancers 12, 1575 (2020).
Yakes, F. M. et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer Ther. 10, 2298–2308 (2011).
Google Scholar
You, W. K. et al. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res. 71, 4758–4768 (2011).
Google Scholar
Torres, K. E. et al. Activated MET is a molecular prognosticator and potential therapeutic target for malignant peripheral nerve sheath tumors. Clin. Cancer Res. 17, 3943–3955 (2011).
Google Scholar
Choueiri, T. K. et al. Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study. Lancet Oncol. 24, 553–562 (2023).
Google Scholar
Pal, S. K. et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet 397, 695–703 (2021).
Google Scholar
Apolo, A. B. et al. Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial. Lancet Oncol. 21, 1099–1109 (2020).
Google Scholar
Smith, D. C. et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J. Clin. Oncol. 31, 412–419 (2013).
Google Scholar
Kelley, R. K. et al. Efficacy and safety of cabozantinib for patients with advanced hepatocellular carcinoma based on albumin-bilirubin grade. Br. J. Cancer 126, 569–575 (2022).
Google Scholar
Tolaney, S. M. et al. Cabozantinib for metastatic breast carcinoma: results of a phase II placebo-controlled randomized discontinuation study. Breast Cancer Res. Treat. 160, 305–312 (2016).
Google Scholar
Daud, A. et al. Phase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma. Br. J. Cancer 116, 432–440 (2017).
Google Scholar
Hofmann, F. et al. Targeted therapy for metastatic renal cell carcinoma. Cochrane Database Syst. Rev. 10, CD012796 (2020).
Google Scholar
Fisher, M. J. et al. Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial. Nat. Med. 27, 165–173 (2021).
Google Scholar
van Boxtel, W. et al. Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer. Eur. J. Cancer 161, 128–137 (2022).
Google Scholar
Basch, E. M. et al. Cabozantinib versus mitoxantrone-prednisone in symptomatic metastatic castration-resistant prostate cancer: a randomized phase 3 trial with a primary pain endpoint. Eur. Urol. 75, 929–937 (2019).
Google Scholar
Elisei, R. et al. Cabozantinib in progressive medullary thyroid cancer. J. Clin. Oncol. 31, 3639–3646 (2013).
Google Scholar
Abou-Alfa, G. K. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med. 379, 54–63 (2018).
Google Scholar
Choueiri, T. K. et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 17, 917–927 (2016).
Google Scholar
Spigel, D. R. et al. Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J. Clin. Oncol. 31, 4105–4114 (2013).
Google Scholar
Choueiri, T. K. et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1814–1823 (2015).
Google Scholar
Rabinowits, G. et al. Cabozantinib in patients with advanced merkel cell carcinoma. Oncologist 23, 814–821 (2018).
Google Scholar
Jimenez, C. et al. Cabozantinib in patients with unresectable and progressive metastatic phaeochromocytoma or paraganglioma (the Natalie Trial): a single-arm, phase 2 trial. Lancet Oncol. 25, 658–667 (2024).
Google Scholar
Goyal, L. et al. A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma. Cancer 123, 1979–1988 (2017).
Google Scholar
Dhani, N. C. et al. Phase II trial of cabozantinib in recurrent/metastatic endometrial cancer: a study of the princess Margaret, Chicago, and California Consortia (NCI9322/PHL86). Clin. Cancer Res. 26, 2477–2486 (2020).
Google Scholar
Pal, S. K. et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet 402, 185–195 (2023).
Google Scholar
Lee, C. H. et al. Phase II trial of cabozantinib plus nivolumab in patients with non-clear-cell renal cell carcinoma and genomic correlates. J. Clin. Oncol. 40, 2333–2341 (2022).
Google Scholar
Sharma, S. et al. Small-molecule inhibitor BMS-777607 induces breast cancer cell polyploidy with increased resistance to cytotoxic chemotherapy agents. Mol. Cancer Ther. 12, 725–736 (2013).
Google Scholar
Dai, Y. & Siemann, D. W. BMS-777607, a small-molecule met kinase inhibitor, suppresses hepatocyte growth factor-stimulated prostate cancer metastatic phenotype in vitro. Mol. Cancer Ther. 9, 1554–1561 (2010).
Google Scholar
Cheng, C. T. et al. METRON dual inhibitor, BMS777607, suppresses cholangiocarcinoma cell growth, and METRON upregulation indicates worse prognosis for intrahepatic cholangiocarcinoma patients. Oncol. Rep. 40, 1411–1421 (2018).
Google Scholar
Schroeder, G. M. et al. Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J. Med. Chem. 52, 1251–1254 (2009).
Google Scholar
Roohullah, A. et al. A phase I trial to determine safety and pharmacokinetics of ASLAN002, an oral MET superfamily kinase inhibitor, in patients with advanced or metastatic solid cancers. Invest. New Drugs 36, 886–894 (2018).
Google Scholar
Yan, S. B. et al. LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest. New Drugs 31, 833–844 (2013).
Google Scholar
Zhu, C., Shi, H., Wu, M. & Wei, X. A dual MET/AXL small-molecule inhibitor exerts efficacy against gastric carcinoma through killing cancer cells as well as modulating tumor microenvironment. MedComm 1, 103–118 (2020).
Google Scholar
Yan, S. B. et al. MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping. Invest. New Drugs 36, 536–544 (2018).
Google Scholar
He, A. R. et al. First-in-human phase I study of merestinib, an oral multikinase inhibitor, in patients with advanced cancer. Oncologist 24, e930–e942 (2019).
Google Scholar
Doi, T. et al. Merestinib monotherapy or in combination for japanese patients with advanced and/or metastatic cancer: A phase 1 study. Cancer Med. 10, 6579–6589 (2021).
Google Scholar
Saleh, M. et al. Phase I study of ramucirumab plus merestinib in previously treated metastatic colorectal cancer: safety, preliminary efficacy, and pharmacokinetic findings. Oncologist 25, e1628–e1639 (2020).
Google Scholar
Valle, J. W. et al. Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study. Lancet Oncol. 22, 1468–1482 (2021).
Google Scholar
Belalcazar, A. et al. Targeting the Met pathway in lung cancer. Expert Rev. Anticancer Ther. 12, 519–528 (2012).
Google Scholar
Patnaik, A. et al. Phase I study of glesatinib (MGCD265) in combination with erlotinib or docetaxel in patients with advanced solid tumors. Target Oncol. 17, 125–138 (2022).
Google Scholar
Kollmannsberger, C. et al. Phase I study evaluating glesatinib (MGCD265), an inhibitor of MET and AXL, in patients with non-small cell lung cancer and other advanced solid tumors. Target Oncol. 18, 105–118 (2023).
Google Scholar
Hong, D. S. et al. Phase II study investigating the efficacy and safety of glesatinib (MGCD265) in patients with advanced NSCLC containing MET activating alterations. Lung Cancer 190, 107512 (2024).
Google Scholar
Munshi, N. et al. ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol. Cancer Ther. 9, 1544–1553 (2010).
Google Scholar
Kudo, M. et al. A randomized, double-blind, placebo-controlled, phase 3 study of tivantinib in Japanese patients with MET-high hepatocellular carcinoma. Cancer Sci. 111, 3759–3769 (2020).
Google Scholar
Rimassa, L. et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 19, 682–693 (2018).
Google Scholar
Santoro, A. et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 14, 55–63 (2013).
Google Scholar
Rosen, L. S. et al. A first-in-human phase I study of a bivalent MET antibody, emibetuzumab (LY2875358), as monotherapy and in combination with erlotinib in advanced cancer. Clin. Cancer Res. 23, 1910–1919 (2017).
Google Scholar
Sharma, N. & Adjei, A. A. In the clinic: ongoing clinical trials evaluating c-MET-inhibiting drugs. Ther. Adv. Med. Oncol. 3, S37–S50 (2011).
Google Scholar
Spigel, D. R. et al. Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung. J. Clin. Oncol. 35, 412–420 (2017).
Google Scholar
Rolfo, C., Van Der Steen, N., Pauwels, P. & Cappuzzo, F. Onartuzumab in lung cancer: the fall of Icarus?. Expert Rev. Anticancer Ther. 15, 487–489 (2015).
Google Scholar
Wakelee, H. et al. Efficacy and safety of onartuzumab in combination with first-line bevacizumab- or pemetrexed-based chemotherapy regimens in advanced non-squamous non-small-cell lung cancer. Clin. Lung Cancer 18, 50–59 (2017).
Google Scholar
Camidge, D. R. et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-met protein-overexpressing advanced nonsquamous EGFR-wildtype non-small cell lung cancer in the phase II LUMINOSITY trial. J. Clin. Oncol. 42, 3000–3011 (2024).
Google Scholar
Camidge, D. R. et al. Phase I study of 2- or 3-week dosing of telisotuzumab vedotin, an antibody-drug conjugate targeting c-met, monotherapy in patients with advanced non-small cell lung carcinoma. Clin. Cancer Res. 27, 5781–5792 (2021).
Google Scholar
Wang, J. et al. ABBV-399, a c-met antibody-drug conjugate that targets both MET-amplified and c-Met-overexpressing tumors, irrespective of MET pathway dependence. Clin. Cancer Res. 23, 992–1000 (2017).
Google Scholar
Strickler, J. H. et al. First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody-drug conjugate targeting c-met, in patients with advanced solid tumors. J. Clin. Oncol. 36, 3298–3306 (2018).
Google Scholar
Camidge, D. R. et al. Phase Ib study of telisotuzumab vedotin in combination with erlotinib in patients with c-met protein-expressing non-small-cell lung cancer. J. Clin. Oncol. 41, 1105–1115 (2023).
Google Scholar
Casaletto, J. B. et al. MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM. Proc. Natl. Acad. Sci. USA 116, 7533–7542 (2019).
Google Scholar
D’Arcangelo, M. & Cappuzzo, F. Focus on the potential role of ficlatuzumab in the treatment of non-small cell lung cancer. Biologics 7, 61–68 (2013).
Google Scholar
Kumar, D. et al. Mitigation of tumor-associated fibroblast-facilitated head and neck cancer progression with anti-hepatocyte growth factor antibody ficlatuzumab. JAMA Otolaryngol. Head. Neck Surg. 141, 1133–1139 (2015).
Google Scholar
Wang, V. E. et al. Inhibition of MET signaling with ficlatuzumab in combination with chemotherapy in refractory AML: clinical outcomes and high-dimensional analysis. Blood Cancer Discov. 2, 434–449 (2021).
Google Scholar
Bauman, J. E. et al. Phase I study of ficlatuzumab and cetuximab in cetuximab-resistant, recurrent/metastatic head and neck cancer. Cancers (Basel). 12, 1537 (2020).
Mok, T. S. et al. A Randomized phase 2 study comparing the combination of ficlatuzumab and gefitinib with gefitinib alone in asian patients with advanced stage pulmonary adenocarcinoma. J. Thorac. Oncol. 11, 1736–1744 (2016).
Google Scholar
Bauman, J. E. et al. Randomized phase II trial of ficlatuzumab with or without cetuximab in pan-refractory, recurrent/metastatic head and neck cancer. J. Clin. Oncol. 41, 3851–3862 (2023).
Google Scholar
Perez, K. et al. Phase Ib and expansion study of gemcitabine, nab-paclitaxel, and ficlatuzumab in patients with metastatic pancreatic cancer. Oncologist 28, 425–432 (2023).
Google Scholar
Burgess, T. L. et al. Biochemical characterization of AMG 102: a neutralizing, fully human monoclonal antibody to human and nonhuman primate hepatocyte growth factor. Mol. Cancer Ther. 9, 400–409 (2010).
Google Scholar
Doshi, S. et al. Rilotumumab exposure-response relationship in patients with advanced or metastatic gastric cancer. Clin. Cancer Res. 21, 2453–2461 (2015).
Google Scholar
Gordon, M. S. et al. Safety, pharmacokinetics, and pharmacodynamics of AMG 102, a fully human hepatocyte growth factor-neutralizing monoclonal antibody, in a first-in-human study of patients with advanced solid tumors. Clin. Cancer Res. 16, 699–710 (2010).
Google Scholar
Tarhini, A. A. et al. Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non-small cell lung cancer. Cancer 123, 2936–2944 (2017).
Google Scholar
Iveson, T. et al. Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol. 15, 1007–1018 (2014).
Google Scholar
Catenacci, D. V. T. et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 18, 1467–1482 (2017).
Google Scholar
Martin, L. P. et al. A phase II evaluation of AMG 102 (rilotumumab) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol. Oncol. 132, 526–530 (2014).
Google Scholar
Ryan, C. J. et al. Targeted MET inhibition in castration-resistant prostate cancer: a randomized phase II study and biomarker analysis with rilotumumab plus mitoxantrone and prednisone. Clin. Cancer Res. 19, 215–224 (2013).
Google Scholar
Song, S. W. et al. Inhibition of tumor growth in a mouse xenograft model by the humanized anti-HGF monoclonal antibody YYB-101 produced in a large-scale CHO cell culture. J. Microbiol. Biotechnol. 23, 1327–1338 (2013).
Google Scholar
Kim, S. et al. Efficient selection of antibodies reactive to homologous epitopes on human and mouse hepatocyte growth factors by next-generation sequencing-based analysis of the B cell repertoire. Int. J. Mol. Sci. 20, 417 (2019).
Sa, J. K. et al. Identification of genomic and molecular traits that present therapeutic vulnerability to HGF-targeted therapy in glioblastoma. Neuro Oncol. 21, 222–233 (2019).
Google Scholar
Kim, H. et al. Preclinical development of a humanized neutralizing antibody targeting HGF. Exp. Mol. Med. 49, e309 (2017).
Google Scholar
Kim, H. J. et al. Humanized anti-hepatocyte growth factor monoclonal antibody (YYB-101) inhibits ovarian cancer progression. Front. Oncol. 9, 571 (2019).
Google Scholar
Kim, H. J. & Heo, K. YYB-101, a humanized antihepatocyte growth factor monoclonal antibody, inhibits ovarian cancer cell motility and proliferation. Anticancer Res. 41, 671–678 (2021).
Google Scholar
Okamoto, W. et al. TAK-701, a humanized monoclonal antibody to hepatocyte growth factor, reverses gefitinib resistance induced by tumor-derived HGF in non-small cell lung cancer with an EGFR mutation. Mol. Cancer Ther. 9, 2785–2792 (2010).
Google Scholar
Houghton, P. J. et al. Initial testing (Stage 1) of TAK-701, a humanized hepatocyte growth factor binding antibody, by the pediatric preclinical testing program. Pediatr. Blood Cancer 61, 380–382 (2014).
Google Scholar
Hayashi, T. et al. Binding of an RNA aptamer and a partial peptide of a prion protein: crucial importance of water entropy in molecular recognition. Nucleic Acids Res. 42, 6861–6875 (2014).
Google Scholar
Hermann, T. & Patel, D. J. Adaptive recognition by nucleic acid aptamers. Science 287, 820–825 (2000).
Google Scholar
Zhu, C., Wei, Y. & Wei, X. AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications. Mol. Cancer 18, 153 (2019).
Google Scholar
Lee, M. et al. Recent advances and prospects of nucleic acid therapeutics for anti-cancer therapy. Molecules. 29, 447 (2024).
Cerchia, L. et al. Targeting Axl with an high-affinity inhibitory aptamer. Mol. Ther. 20, 2291–2303 (2012).
Google Scholar
Esposito, C. L., Catuogno, S., de Franciscis, V. & Cerchia, L. New insight into clinical development of nucleic acid aptamers. Discov. Med. 11, 487–496 (2011).
Google Scholar
Ueki, R. & Sando, S. A DNA aptamer to c-Met inhibits cancer cell migration. Chem. Commun. 50, 13131–13134 (2014).
Google Scholar
Zhang, Y. et al. Targeting c-met receptor tyrosine kinase by the DNA aptamer SL1 as a potential novel therapeutic option for myeloma. J. Cell Mol. Med. 22, 5978–5990 (2018).
Google Scholar
Petrelli, A. et al. Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity. Proc. Natl. Acad. Sci. USA 103, 5090–5095 (2006).
Google Scholar
Prat, M. et al. C-terminal truncated forms of Met, the hepatocyte growth factor receptor. Mol. Cell Biol. 11, 5954–5962 (1991).
Google Scholar
Coxon, A. et al. Soluble c-Met receptors inhibit phosphorylation of c-Met and growth of hepatocyte growth factor: c-Met-dependent tumors in animal models. Mol. Cancer Ther. 8, 1119–1125 (2009).
Google Scholar
Basilico, C. et al. A high affinity hepatocyte growth factor-binding site in the immunoglobulin-like region of Met. J. Biol. Chem. 283, 21267–21277 (2008).
Google Scholar
Yang, J. J. et al. Soluble c-Met protein as a susceptible biomarker for gastric cancer risk: a nested case-control study within the Korean Multicenter Cancer Cohort. Int J. Cancer 132, 2148–2156 (2013).
Google Scholar
Shanmugam, M. K. et al. The multifaceted role of curcumin in cancer prevention and treatment. Molecules 20, 2728–2769 (2015).
Google Scholar
Shanmugam, M. K., Kannaiyan, R. & Sethi, G. Targeting cell signaling and apoptotic pathways by dietary agents: role in the prevention and treatment of cancer. Nutr. Cancer 63, 161–173 (2011).
Google Scholar
Aggarwal, B. B., Kumar, A. & Bharti, A. C. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 23, 363–398 (2003).
Google Scholar
Sharma, R. A. et al. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin. Cancer Res. 10, 6847–6854 (2004).
Google Scholar
Ohnishi, Y. et al. Curcumin inhibits epithelial-mesenchymal transition in oral cancer cells via c-Met blockade. Oncol. Lett. 19, 4177–4182 (2020).
Google Scholar
Simonetti, S. et al. Detection of EGFR mutations with mutation-specific antibodies in stage IV non-small-cell lung cancer. J. Transl. Med. 8, 135 (2010).
Google Scholar
Okabe, T. et al. Differential constitutive activation of the epidermal growth factor receptor in non-small cell lung cancer cells bearing EGFR gene mutation and amplification. Cancer Res. 67, 2046–2053 (2007).
Google Scholar
Seol, D. W., Chen, Q. & Zarnegar, R. Transcriptional activation of the hepatocyte growth factor receptor (c-met) gene by its ligand (hepatocyte growth factor) is mediated through AP-1. Oncogene 19, 1132–1137 (2000).
Google Scholar
Yamauchi, Y., Izumi, Y., Yamamoto, J. & Nomori, H. Coadministration of erlotinib and curcumin augmentatively reduces cell viability in lung cancer cells. Phytother. Res. 28, 728–735 (2014).
Google Scholar
Shin, H. J., Lee, S. & Jung, H. J. A curcumin derivative hydrazinobenzoylcurcumin suppresses stem-like features of glioblastoma cells by targeting Ca(2 + ) /calmodulin-dependent protein kinase II. J. Cell Biochem. 120, 6741–6752 (2019).
Google Scholar
Shanmugam, M. K. et al. Potential role of natural compounds as anti-angiogenic agents in cancer. Curr. Vasc. Pharm. 15, 503–519 (2017).
Google Scholar
Kannaiyan, R., Shanmugam, M. K. & Sethi, G. Molecular targets of celastrol derived from thunder of god vine: potential role in the treatment of inflammatory disorders and cancer. Cancer Lett. 303, 9–20 (2011).
Google Scholar
Jiang, H. L. et al. Celastrol exerts synergistic effects with PHA-665752 and inhibits tumor growth of c-Met-deficient hepatocellular carcinoma in vivo. Mol. Biol. Rep. 40, 4203–4209 (2013).
Google Scholar
Mohan, C. D. et al. c-MET pathway in human malignancies and its targeting by natural compounds for cancer therapy. Phytomedicine 128, 155379 (2024).
Google Scholar
Lambert, J. D. & Yang, C. S. Mechanisms of cancer prevention by tea constituents. J. Nutr. 133, 3262S–3267S (2003).
Google Scholar
Crespy, V. & Williamson, G. A review of the health effects of green tea catechins in in vivo animal models. J. Nutr. 134, 3431S–3440S (2004).
Google Scholar
Kwak, I. H. et al. Epigallocatechin-3-gallate inhibits paracrine and autocrine hepatocyte growth factor/scatter factor-induced tumor cell migration and invasion. Exp. Mol. Med. 43, 111–120 (2011).
Google Scholar
Duhon, D. et al. The polyphenol epigallocatechin-3-gallate affects lipid rafts to block activation of the c-Met receptor in prostate cancer cells. Mol. Carcinog. 49, 739–749 (2010).
Google Scholar
Larsen, C. A. & Dashwood, R. H. (–)-Epigallocatechin-3-gallate inhibits Met signaling, proliferation, and invasiveness in human colon cancer cells. Arch. Biochem. Biophys. 501, 52–57 (2010).
Google Scholar
Larsen, C. A. & Dashwood, R. H. Suppression of Met activation in human colon cancer cells treated with (-)-epigallocatechin-3-gallate: minor role of hydrogen peroxide. Biochem. Biophys. Res. Commun. 389, 527–530 (2009).
Google Scholar
Milligan, S. A. et al. The green tea polyphenol EGCG potentiates the antiproliferative activity of c-Met and epidermal growth factor receptor inhibitors in non-small cell lung cancer cells. Clin. Cancer Res. 15, 4885–4894 (2009).
Google Scholar
Lim, Y. C. et al. (-)-Epigallocatechin-3-gallate (EGCG) inhibits HGF-induced invasion and metastasis in hypopharyngeal carcinoma cells. Cancer Lett. 271, 140–152 (2008).
Google Scholar
Bigelow, R. L. & Cardelli, J. A. The green tea catechins, (-)-Epigallocatechin-3-gallate (EGCG) and (-)-Epicatechin-3-gallate (ECG), inhibit HGF/Met signaling in immortalized and tumorigenic breast epithelial cells. Oncogene 25, 1922–1930 (2006).
Google Scholar
Zhu, K. & Wang, W. Green tea polyphenol EGCG suppresses osteosarcoma cell growth through upregulating miR-1. Tumour Biol. 37, 4373–4382 (2016).
Google Scholar
Sakamoto, K. M. et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. USA 98, 8554–8559 (2001).
Google Scholar
Mares, A. et al. Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2. Commun. Biol. 3, 140 (2020).
Google Scholar
Burslem, G. M. et al. The advantages of targeted protein degradation over inhibition: an RTK case study. Cell Chem. Biol. 25, 67–77 e63 (2018).
Google Scholar
Bond, M. J. et al. Targeted degradation of oncogenic KRAS(G12C) by VHL-recruiting PROTACs. ACS Cent. Sci. 6, 1367–1375 (2020).
Google Scholar
Han, X. et al. Discovery of ARD-69 as a highly potent proteolysis targeting chimera (PROTAC) degrader of androgen receptor (AR) for the treatment of prostate cancer. J. Med. Chem. 62, 941–964 (2019).
Google Scholar
Guo, J., Liu, J. & Wei, W. Degrading proteins in animals: “PROTAC“tion goes in vivo. Cell Res. 29, 179–180 (2019).
Google Scholar
Bondeson, D. P. et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11, 611–617 (2015).
Google Scholar
Bekes, M., Langley, D. R. & Crews, C. M. PROTAC targeted protein degraders: the past is prologue. Nat. Rev. Drug Discov. 21, 181–200 (2022).
Google Scholar
Zhou, H. et al. Structure-based discovery of SD-36 as a potent, selective, and efficacious PROTAC degrader of STAT3 protein. J. Med. Chem. 62, 11280–11300 (2019).
Google Scholar
Han, X. et al. Strategies toward discovery of potent and orally bioavailable proteolysis targeting chimera degraders of androgen receptor for the treatment of prostate cancer. J. Med. Chem. 64, 12831–12854 (2021).
Google Scholar
Hu, J. et al. Discovery of ERD-308 as a highly potent proteolysis targeting chimera (PROTAC) degrader of estrogen receptor (ER). J. Med. Chem. 62, 1420–1442 (2019).
Google Scholar
Zhang, C. et al. Proteolysis targeting chimeras (PROTACs) of anaplastic lymphoma kinase (ALK). Eur. J. Med. Chem. 151, 304–314 (2018).
Google Scholar
Wu, X. et al. Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders. Nat. Cancer 2, 429–443 (2021).
Google Scholar
Cheng, M. et al. Discovery of potent and selective epidermal growth factor receptor (EGFR) Bifunctional small-molecule degraders. J. Med. Chem. 63, 1216–1232 (2020).
Google Scholar
Xie, S. et al. Development of alectinib-based PROTACs as novel potent degraders of anaplastic lymphoma kinase (ALK). J. Med. Chem. 64, 9120–9140 (2021).
Google Scholar
Yang, J. et al. Discovery of a highly potent and selective dual PROTAC degrader of CDK12 and CDK13. J. Med. Chem. 65, 11066–11083 (2022).
Google Scholar
Li, J. et al. Discovery of small-molecule degraders of the CDK9-cyclin T1 complex for targeting transcriptional addiction in prostate cancer. J. Med. Chem. 65, 11034–11057 (2022).
Google Scholar
Wang, L. et al. Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy. Nat. Chem. Biol. 17, 567–575 (2021).
Google Scholar
Sun, Y. et al. PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies. Cell Res. 28, 779–781 (2018).
Google Scholar
Zhang, X. et al. Design and synthesis of selective degraders of EGFR(L858R/T790M) mutant. Eur. J. Med. Chem. 192, 112199 (2020).
Google Scholar
Wang, J. et al. EZH2 noncanonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis. Nat. Cell Biol. 24, 384–399 (2022).
Google Scholar
Meng, F. et al. Discovery of a first-in-class degrader for nuclear receptor binding SET domain protein 2 (NSD2) and Ikaros/Aiolos. J. Med. Chem. 65, 10611–10625 (2022).
Google Scholar
Liu, Z. et al. Design and synthesis of EZH2-based PROTACs to degrade the PRC2 complex for targeting the noncatalytic activity of EZH2. J. Med. Chem. 64, 2829–2848 (2021).
Google Scholar
Qin, C. et al. Discovery of QCA570 as an exceptionally potent and efficacious proteolysis targeting chimera (PROTAC) degrader of the bromodomain and extra-terminal (BET) proteins capable of inducing complete and durable tumor regression. J. Med. Chem. 61, 6685–6704 (2018).
Google Scholar
Bollu, L. R. et al. Identification and characterization of a novel indoleamine 2,3-dioxygenase 1 protein degrader for glioblastoma. J. Med. Chem. 65, 15642–15662 (2022).
Google Scholar
Liu, J. et al. Novel CRBN-recruiting proteolysis-targeting chimeras as degraders of stimulator of interferon genes with in vivo anti-inflammatory efficacy. J. Med. Chem. 65, 6593–6611 (2022).
Google Scholar
Wang, Y. et al. In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC). Bioorg. Chem. 111, 104833 (2021).
Google Scholar
Fernandes, M. et al. When the MET receptor kicks in to resist targeted therapies. Oncogene 40, 4061–4078 (2021).
Google Scholar
Chen, J. J. et al. Crizotinib-based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation. Cancer Sci. 114, 1958–1971 (2023).
Google Scholar
Li, P. et al. Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations. Acta Pharm. Sin. B 13, 2715–2735 (2023).
Google Scholar
Bondeson, D. P. et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem. Biol. 25, 78–87 e75 (2018).
Google Scholar
Mallareddy, J. R. et al. Fluorescence based live cell imaging identifies exon 14 skipped hepatocyte growth factor receptor (MET) degraders. RSC Adv. 15, 10419–10425 (2025).
Google Scholar
Ying, S. et al. Selective and orally bioavailable c-Met PROTACs for the treatment of c-met-addicted cancer. J. Med. Chem. 67, 17053–17069 (2024).
Google Scholar
Sachkova, A. A. et al. Design, synthesis and in vitro investigation of cabozantinib-based PROTACs to target c-met kinase. Pharmaceutics. 14, 2829 (2022).
Goracci, L. et al. Understanding the metabolism of proteolysis targeting chimeras (PROTACs): the next step toward pharmaceutical applications. J. Med. Chem. 63, 11615–11638 (2020).
Google Scholar
Han, Y. et al. Targeting MET in NSCLC: an ever-expanding territory. JTO Clin. Res. Rep. 5, 100630 (2024).
Google Scholar
Scagliotti, G. et al. Phase III multinational, randomized, double-blind, placebo-controlled study of tivantinib (ARQ 197) plus erlotinib versus erlotinib alone in previously treated patients with locally advanced or metastatic nonsquamous non-small-cell lung cancer. J. Clin. Oncol. 33, 2667–2674 (2015).
Google Scholar
Reis, H. et al. MET expression in advanced non-small-cell lung cancer: effect on clinical outcomes of chemotherapy, targeted therapy, and immunotherapy. Clin. Lung Cancer 19, e441–e463 (2018).
Google Scholar
Engstrom, L. D. et al. Glesatinib exhibits antitumor activity in lung cancer models and patients harboring MET Exon 14 mutations and overcomes mutation-mediated resistance to type I MET inhibitors in nonclinical models. Clin. Cancer Res. 23, 6661–6672 (2017).
Google Scholar
Finocchiaro, G. et al. Prognostic and predictive value of MET deregulation in non-small cell lung cancer. Ann. Transl. Med. 3, 83 (2015).
Google Scholar
Coleman, N. et al. Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer. ESMO Open 6, 100319 (2021).
Google Scholar
Tanaka, A. et al. Co-existence of positive MET FISH status with EGFR mutations signifies poor prognosis in lung adenocarcinoma patients. Lung Cancer 75, 89–94 (2012).
Google Scholar
Tong, J. H. et al. MET amplification and exon 14 splice site mutation define unique molecular subgroups of non-small cell lung carcinoma with poor prognosis. Clin. Cancer Res. 22, 3048–3056 (2016).
Google Scholar
Lai, G. G. Y. et al. Clonal MET amplification as a determinant of tyrosine kinase inhibitor resistance in epidermal growth factor receptor-mutant non-small-cell lung cancer. J. Clin. Oncol. 37, 876–884 (2019).
Google Scholar
Cappuzzo, F. et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J. Clin. Oncol. 27, 1667–1674 (2009).
Google Scholar
Cappuzzo, F. et al. MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients. Ann. Oncol. 20, 298–304 (2009).
Google Scholar
Noonan, S. A. et al. Identifying the appropriate FISH criteria for defining MET copy number-driven lung adenocarcinoma through oncogene overlap analysis. J. Thorac. Oncol. 11, 1293–1304 (2016).
Google Scholar
Recondo, G., Che, J., Janne, P. A. & Awad, M. M. Targeting MET dysregulation in cancer. Cancer Discov. 10, 922–934 (2020).
Google Scholar
Drilon, A., Cappuzzo, F., Ou, S. I. & Camidge, D. R. Targeting MET in lung cancer: will expectations finally be MET?. J. Thorac. Oncol. 12, 15–26 (2017).
Google Scholar
Jordan, E. J. et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 7, 596–609 (2017).
Google Scholar
Zheng, Z. et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat. Med. 20, 1479–1484 (2014).
Google Scholar
Peng, L. X. et al. MET amplification identified by next-generation sequencing and its clinical relevance for MET inhibitors. Exp. Hematol. Oncol. 10, 52 (2021).
Google Scholar
Wilhelm, S. M. et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther. 7, 3129–3140 (2008).
Google Scholar
Wilhelm, S. M. et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64, 7099–7109 (2004).
Google Scholar
Leiser, D. et al. Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation. FEBS Lett. 588, 653–658 (2014).
Google Scholar
Humbert, M. et al. Protective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells. Biochem. Biophys. Res. Commun. 431, 264–269 (2013).
Google Scholar
Hassan, W., Chitcholtan, K., Sykes, P. & Garrill, A. A combination of two receptor tyrosine kinase inhibitors, canertinib and PHA665752 compromises ovarian cancer cell growth in 3D cell models. Oncol. Ther. 4, 257–274 (2016).
Google Scholar
Yang, Y. et al. A selective small molecule inhibitor of c-Met, PHA-665752, reverses lung premalignancy induced by mutant K-ras. Mol. Cancer Ther. 7, 952–960 (2008).
Google Scholar
Nessling, M. et al. Mapping of chromosomal imbalances in gastric adenocarcinoma revealed amplified protooncogenes MYCN, MET, WNT2, and ERBB2. Genes Chromosomes Cancer 23, 307–316 (1998).
Google Scholar
Sakakura, C. et al. Gains, losses, and amplifications of genomic materials in primary gastric cancers analyzed by comparative genomic hybridization. Genes Chromosomes Cancer 24, 299–305 (1999).
Google Scholar
Kuniyasu, H. et al. Frequent amplification of the c-met gene in scirrhous type stomach cancer. Biochem. Biophys. Res. Commun. 189, 227–232 (1992).
Google Scholar
Fang, M. M. et al. Molecular features and clinical outcomes of EGFR-mutated, MET-amplified non-small-cell lung cancer after resistance to dual-targeted therapy. Ther. Adv. Med. Oncol. 16, 17588359241234504 (2024).
Google Scholar
Knight, J. F. et al. Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer. Proc. Natl. Acad. Sci. USA 110, E1301–E1310 (2013).
Google Scholar
Jung, H. Y., Joo, H. J., Park, J. K. & Kim, Y. H. The blocking of c-met signaling induces apoptosis through the increase of p53 protein in lung cancer. Cancer Res. Treat. 44, 251–261 (2012).
Google Scholar
Takeda, S. et al. HGF-MET signals via the MLL-ETS2 complex in hepatocellular carcinoma. J. Clin. Invest. 123, 3154–3165 (2013).
Google Scholar
Lin, H. C. et al. Fas ligand enhances malignant behavior of tumor cells through interaction with Met, hepatocyte growth factor receptor, in lipid rafts. J. Biol. Chem. 287, 20664–20673 (2012).
Google Scholar
Foveau, B. et al. Amplification of apoptosis through sequential caspase cleavage of the MET tyrosine kinase receptor. Cell Death Differ. 14, 752–764 (2007).
Google Scholar
Togashi, Y. et al. MET gene exon 14 deletion created using the CRISPR/Cas9 system enhances cellular growth and sensitivity to a MET inhibitor. Lung Cancer 90, 590–597 (2015).
Google Scholar
Ding, L. et al. SAHA triggered MET activation contributes to SAHA tolerance in solid cancer cells. Cancer Lett. 356, 828–836 (2015).
Google Scholar
