Herbst RS. Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys. 2004;59:21–6.
Google Scholar
Sabbah DA, Hajjo R, Sweidan K. Review on Epidermal Growth Factor Receptor (EGFR) Structure, Signaling Pathways, Interactions, and Recent Updates of EGFR Inhibitors. Curr Top Med Chem. 2020;20:815–34.
Google Scholar
Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Mol Oncol. 2018;12:3–20.
Google Scholar
Kumagai S, Koyama S, Nishikawa H. Antitumour immunity regulated by aberrant ERBB family signalling. Nat Rev Cancer. 2021;21:181–97.
Google Scholar
Leonetti A, Assaraf YG, Veltsista PD, El Hassouni B, Tiseo M, Giovannetti E. MicroRNAs as a drug resistance mechanism to targeted therapies in EGFR-mutated NSCLC: Current implications and future directions. Drug Resistance Updates. 2019;42:1–11.
Google Scholar
Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. 2010;10:760–74.
Google Scholar
Gridelli C, Rossi A, Carbone DP, Guarize J, Karachaliou N, Mok T, et al. Non-small-cell lung cancer. Nat Rev Dis Prim. 2015;1:15009.
Google Scholar
Fujino S, Enokibori T, Tezuka N, Asada Y, Inoue S, Kato H, et al. A comparison of epidermal growth factor receptor levels and other prognostic parameters in non-small cell lung cancer. Eur J Cancer. 1996;32:2070–4.
Google Scholar
Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7:169–81.
Google Scholar
Robichaux JP, Le X, Vijayan RSK, Hicks JK, Heeke S, Elamin YY, et al. Structure-based classification predicts drug response in EGFR-mutant NSCLC. Nature. 2021;597:732–7.
Google Scholar
Cataldo VD, Gibbons DL, Pérez-Soler R, Quintás-Cardama A. Treatment of non–small-cell lung cancer with erlotinib or gefitinib. New Engl J Med. 2011;364:947–55.
Google Scholar
Yang JC-H, Wu Y-L, Schuler M, Sebastian M, Popat S, Yamamoto N, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16:141–51.
Google Scholar
Berz D, Raymond VM, Garst JH, Erlander MG. Non-invasive urine testing of EGFR activating mutation and T790M resistance mutation in non-small cell lung cancer. Exp Hematol Oncol. 2016;5:24.
Google Scholar
Huang L, Fu L. Mechanisms of resistance to EGFR tyrosine kinase inhibitors. Acta Pharmaceut Sin B. 2015;5:390–401.
Google Scholar
Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M. et al. EGFR Mutation and resistance of non–small-cell lung cancer to gefitinib. New Engl J Med. 2005;352:786–92.
Google Scholar
Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. 2020;382:41–50.
Google Scholar
Soria J-C, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KiH, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. N Engl J Med. 2018;378:113–25.
Google Scholar
Zhou W, Ercan D, Chen L, Yun C-H, Li D, Capelletti M, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature. 2009;462:1070–4.
Google Scholar
Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21:560–2.
Google Scholar
Yu HA, Tian SK, Drilon AE, Borsu L, Riely GJ, Arcila ME, et al. Acquired Resistance of EGFR-Mutant Lung Cancer to a T790M-Specific EGFR Inhibitor: Emergence of a Third Mutation (C797S) in the EGFR Tyrosine Kinase Domain. JAMA Oncol. 2015;1:982–4.
Google Scholar
Niederst MJ, Hu H, Mulvey HE, Lockerman EL, Garcia AR, Piotrowska Z. et al. The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies. Clin Cancer Res. 2015;21:3924–33.
Google Scholar
Planchard D, Loriot Y, André F, Gobert A, Auger N, Lacroix L, et al. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015;26:2073–8.
Google Scholar
Su C, Sun SY. Fourth-generation epidermal growth factor receptor-tyrosine kinases inhibitors: hope and challenges. Transl Cancer Res. 2024;13:3929–34.
Google Scholar
Corvaja C, Passaro A, Attili I, Aliaga PT, Spitaleri G, Signore ED. et al. Advancements in fourth-generation EGFR TKIs in EGFR-mutant NSCLC: Bridging biological insights and therapeutic development. Cancer Treatment Rev. 2024;130:102824.
Google Scholar
Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022;21:181–200.
Google Scholar
Hinterndorfer M, Spiteri VA, Ciulli A, Winter GE. Targeted protein degradation for cancer therapy. Nat Rev Cancer. 2025;25:493–516.
Google Scholar
Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci USA. 2001;98:8554–9.
Google Scholar
Clift D, McEwan WA, Labzin LI, Konieczny V, Mogessie B, James LC, et al. A Method for the Acute and Rapid Degradation of Endogenous Proteins. Cell. 2017;171:1692–706.e1618.
Google Scholar
Banik SM, Pedram K, Wisnovsky S, Ahn G, Riley NM, Bertozzi CR. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature. 2020;584:291–7.
Google Scholar
Ahn G, Banik SM, Miller CL, Riley NM, Cochran JR, Bertozzi CR. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nat Chem Biol. 2021;17:937–46.
Google Scholar
Pance K, Gramespacher JA, Byrnes JR, Salangsang F, Serrano J-AC, Cotton AD, et al. Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins. Nat Biotechnol. 2023;41:273–81.
Google Scholar
Huang B, Abedi M, Ahn G, Coventry B, Sappington I, Tang C, et al. Designed endocytosis-inducing proteins degrade targets and amplify signals. Nature. 2025;638:796–804.
Google Scholar
Abella JV, Park M. Breakdown of endocytosis in the oncogenic activation of receptor tyrosine kinases. Am J Physiol Endocrinol Metab. 2009;296:E973–84.
Google Scholar
Wells A, Welsh JB, Lazar CS, Wiley HS, Gill GN, Rosenfeld MG. Ligand-induced transformation by a noninternalizing epidermal growth factor receptor. Science. 1990;247:962–4.
Google Scholar
Li JY, Perry SR, Muniz-Medina V, Wang X, Wetzel LK, Rebelatto MC, et al. A Biparatopic HER2-Targeting Antibody-Drug Conjugate Induces Tumor Regression in Primary Models Refractory to or Ineligible for HER2-Targeted Therapy. Cancer Cell. 2016;29:117–29.
Google Scholar
Kast F, Schwill M, Stüber JC, Pfundstein S, Nagy-Davidescu G, Rodríguez JMM, et al. Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action. Nat Commun. 2021;12:3790.
Google Scholar
Kelton C, Wesolowski JS, Soloviev M, Schweickhardt R, Fischer D, Kurosawa E, et al. Anti-EGFR biparatopic-SEED antibody has enhanced combination-activity in a single molecule. Arch Biochem Biophys. 2012;526:219–25.
Google Scholar
Sunada H, Magun BE, Mendelsohn J, MacLeod CL. Monoclonal antibody against epidermal growth factor receptor is internalized without stimulating receptor phosphorylation. Proc Natl Acad Sci. 1986;83:3825–9.
Google Scholar
Nishihara S, Yamaoka T, Ishikawa F, Ohmori T, Ando K, Kusumoto S, et al. Diverse Mechanisms of Resistance against Osimertinib, a Third-Generation EGFR-TKI, in Lung Adenocarcinoma Cells with an EGFR-Activating Mutation. Cells. 2022. https://doi.org/10.3390/cells11142201.
Google Scholar
Ríos-Hoyo A, Moliner L, Arriola E. Acquired Mechanisms of Resistance to Osimertinib—The Next Challenge. Cancers 2022; https://doi.org/10.3390/cancers14081931.
Rogers TF, Zhao F, Huang D, Beutler N, Burns A, He W-t, et al. Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science. 2020;369:956–63.
Google Scholar
Schlothauer T, Herter S, Koller CF, Grau-Richards S, Steinhart V, Spick C, et al. Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions. Protein Eng, Des Select. 2016;29:457–66.
Google Scholar
von Zastrow M, Sorkin A. Mechanisms for Regulating and Organizing Receptor Signaling by Endocytosis. Annu Rev Biochem. 2021;90:709–37.
Google Scholar
Sigismund S, Confalonieri S, Ciliberto A, Polo S, Scita G, Di Fiore PP. Endocytosis and Signaling: Cell Logistics Shape the Eukaryotic Cell Plan. Physiol Rev. 2012;92:273–366.
Google Scholar
Li M, Yu Y. Innate immune receptor clustering and its role in immune regulation. J Cell Sci. 2021;134:jcs249318.
Google Scholar
Domínguez CM, Niemeyer CM. Clustering of Membrane Receptors: Insights from DNA Origami-Based Approaches. Small. 2025;21:2503543.
Google Scholar
Paul D, Stern O, Vallis Y, Dhillon J, Buchanan A, McMahon H. Cell surface protein aggregation triggers endocytosis to maintain plasma membrane proteostasis. Nat Commun. 2023;14:947.
Google Scholar
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and Its Ligands in Tolerance and Immunity. Annu Rev Immunol. 2008;26:677–704.
Google Scholar
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467–77.
Google Scholar
Cherif B, Triki H, Charfi S, Bouzidi L, Kridis WB, Khanfir A, et al. Immune checkpoint molecules B7-H6 and PD-L1 co-pattern the tumor inflammatory microenvironment in human breast cancer. Sci Rep. 2021;11:7550.
Google Scholar
Smit EF, van den Heuvel MM. PD-L1 in non-small-cell lung cancer: the third target for immunotherapy. Lancet. 2016;387:1795–6.
Google Scholar
Liu R, Li H-F, Li S. PD-1-mediated inhibition of T cell activation: Mechanisms and strategies for cancer combination immunotherapy. Cell Insight. 2024;3:100146.
Google Scholar
Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Jänne PA, et al. Clinical Definition of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer. J Clin Oncol. 2009;28:357–60.
Google Scholar
Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K. EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol Cancer. 2018;17:53.
Google Scholar
Ou X, Gao G, Habaz IA, Wang Y. Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies. MedComm. 2024;5:e694.
Google Scholar
Wu D, Sun Q, Tang H, Xiao H, Luo J, Ouyang L, et al. Acquired resistance to tyrosine kinase targeted therapy: mechanism and tackling strategies. Drug Resist Updates. 2025;78:101176.
Google Scholar
Zhang J, Vokes N, Li M, Xu J, Bai H, Wang J, et al. Overcoming EGFR-TKI resistance by targeting the tumor microenvironment. Chin Med J Pulm Crit Care Med. 2024;2:151–61.
Google Scholar
Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121:725–37.
Google Scholar
Radulovic M, Yang C, Stenmark H. Lysosomal membrane homeostasis and its importance in physiology and disease. Nat Rev Mol Cell Biol. 2025;27:71–87.
Google Scholar
Jackson Matthew P, Hewitt Eric W. Cellular proteostasis: degradation of misfolded proteins by lysosomes. Essays Biochem. 2016;60:173–80.
Google Scholar
Shan KS, Musleh Ud Din S, Dalal S, Gonzalez T, Dalal M, Ferraro P et al. Bispecific Antibodies in Solid Tumors: Advances and Challenges. Int J Mol Sci. 2025; https://doi.org/10.3390/ijms26125838.
Wang C, Huang H, Song Z, Li Z, Huang J, Cao L, et al. A novel bispecific antibody CVL006 superior to AK112 for dual targeting of PD-L1 and VEGF in cancer therapy. Antib Therapeut. 2025;8:189–96.
Google Scholar
Zhong T, Zhang L, Huang Z, Pang X, Jin C, Liu W, et al. Design of a fragment crystallizable-engineered tetravalent bispecific antibody targeting programmed cell death-1 and vascular endothelial growth factor with cooperative biological effects. iScience. 2025;28:111722.
Google Scholar
Pang X, Huang Z, Zhong T, Zhang P, Wang ZM, Xia M, et al. Cadonilimab, a tetravalent PD-1/CTLA-4 bispecific antibody with trans-binding and enhanced target binding avidity. mAbs. 2023;15:2180794.
Google Scholar
Blick SKA, Scott LJ. Cetuximab. Drugs. 2007;67:2585–607.
Google Scholar
Zheng B, Wang X, Wei M, Wang Q, Li J, Bi L, et al. First-line cetuximab versus bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a systematic review and meta-analysis. BMC Cancer. 2019;19:280.
Google Scholar
Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au H-J et al. Cetuximab for the Treatment of Colorectal Cancer. New Engl J Med. 357:2040–8.
Muraro E, Fanetti G, Lupato V, Giacomarra V, Steffan A, Gobitti C, et al. Cetuximab in locally advanced head and neck squamous cell carcinoma: Biological mechanisms involved in efficacy, toxicity and resistance. Crit Rev Oncol Hematol. 2021;164:103424.
Google Scholar
Marei H, Tsai W-TK, Kee Y-S, Ruiz K, He J, Cox C, et al. Antibody targeting of E3 ubiquitin ligases for receptor degradation. Nature. 2022;610:182–9.
Google Scholar
Cotton AD, Nguyen DP, Gramespacher JA, Seiple IB, Wells JA. Development of Antibody-Based PROTACs for the Degradation of the Cell-Surface Immune Checkpoint Protein PD-L1. J Am Chem Soc. 2021;143:593–8.
Google Scholar
Lewis GD, Li G, Guo J, Yu S-F, Fields CT, Lee G, et al. The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results. Nat Commun. 2024;15:466.
Google Scholar
Liu D, Liu B, Li Z, Gao B, Zhang X, Ruan J, et al. A pooled analysis of JSKN003, a biparatopic anti-HER2 antibody conjugate (ADC), in patients with advanced HER2-overexpressing (IHC 3+) gastrointestinal tumors. J Clin Oncol. 2025;43:3022.
Google Scholar
Wang T-H, Wu C-C, Huang K-Y, Leu Y-L, Yang S-C, Chen C-L et al. Integrated Omics Analysis of Non-Small-Cell Lung Cancer Cells Harboring the EGFR C797S Mutation Reveals the Potential of AXL as a Novel Therapeutic Target in TKI-Resistant Lung Cancer. Cancers 2021; https://doi.org/10.3390/cancers13010111.
