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Overcoming therapy resistance in EGFR-mutant lung cancer

Abstract

Tyrosine kinase inhibitors (TKIs) have dramatically changed the clinical prospects of patients with non-small cell lung cancer harboring epidermal growth factor receptor (EGFR)-activating mutations. Despite prolonged disease control and high tumor response rates, all patients eventually progress on EGFR TKI treatment. Here, we review the mechanisms of acquired EGFR TKI resistance, the methods for monitoring its appearance, as well as current and future efforts to define treatment strategies to overcome resistance.

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Fig. 1: Overview of the EGFR signal transduction pathway model, with a focus on the acquired resistance mechanisms and related potential treatment strategies.
Fig. 2: Mechanisms of resistance to osimertinib.
Fig. 3: Specific EGFR-dependent (on-target) mutations acquired after osimertinib treatment.

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A.P. received honoraria for consulting, advising or lecturing from AstraZeneca, Agilent/Dako, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Pfizer and Roche/Genentech. P.A.J. is a consultant at AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Sanofi Oncology, Takeda Oncology, Pfizer, Roche/Genentech, Biocartis, Silicon Therapeutics, Esai, Bayer, ACEA Biosciences, Eli Lilly, Araxes Pharma and SFJ Pharmaceuticals; is a Scientific Advisory Board member for Voronoi, Biocartis, Mirati Therapeutics, Ignyta and Loxo Oncology; reports receiving commercial research grants from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Astellas, Eli Lilly, Revolution Medicines and Takeda Oncology; has ownership interest (including patents) in Gatekeeper Pharmaceuticals and Loxo Oncology; and reports receiving other remuneration from LabCorp. T.M. reports grant/research support from AstraZeneca, Bristol Myers Squibb, Clovis Oncology, G1 Therapeutics, MSD, Merck Serono, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, Takeda and Xcovery; speaker’s fees from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, InMed Medical Communication, MSD, Novartis, Pfizer, prIME Oncology, Roche/Genentech, Taiho and Takeda Oncology; honoraria from AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Blueprint Medicines Corporation, Bristol Myers Squibb, Celgene, CStone Pharmaceuticals, Daiichi Sankyo, Eli Lilly, Fishawack Facilitate, Hengrui Therapeutics, Ignyta, Incyte Corporation, InMed Medical Communication, IQVIA, Janssen, Loxo Oncology, Merck Serono, MSD, MORE Health, Novartis, OncoGenex Pharmaceuticals, OrigiMed, PeerVoice, Pfizer, prIME Oncology, Roche/Genentech, Sanofi-Aventis R&D, SFJ Pharmaceuticals, Takeda Pharmaceuticals (Hong Kong), Vertex Pharmaceuticals, Yuhan Corporation, Medscape/WebMD (medical education/continuing medical education activities), PeerVoice (independent medical education) and prIME Oncology (medical education); shares in Hutchison Chi-Med and Sanomics; stock options in Clearbridge Biomedics (now Biolidics), Loxo Oncology, OrigiMed and Virtus Medical Group; an advisory role for AbbVie, ACEA Pharma, Amgen, AstraZeneca, Bayer, Blueprint Medicines Corporation, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cirina, CStone Pharmaceuticals, Daiichi Sankyo, Eli Lilly, Fishawack Facilitate, G1 Therapeutics, GeneDecode (uncompensated), Hengrui Therapeutics, Hutchison Chi-Med, Ignyta, Incyte Corporation, IQVIA, Janssen, Loxo Oncology, Lunit, Merck Serono, Merck Sharp & Dohme, Novartis, OncoGenex Technologies, OrigiMed, Pfizer, Roche/Genentech, Sanofi-Aventis R&D, SFJ Pharmaceutical, Takeda Oncology, Vertex Pharmaceuticals, Virtus Medical Group and Yuhan Corporation; board of directors/leadership roles (remunerated) for AstraZeneca and Hutchison Chi-Med; and board of directors/leadership roles (non-remunerated) for the American Society of Clinical Oncology (ASCO), Asian Thoracic Oncology Research Group (ATORG), Chinese Lung Cancer Research Foundation Limited (CLCRF), Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Fund (HKCF), Hong Kong Cancer Therapy Society (HKCTS), International Association for the Study of Lung Cancer (IASLC) and St. Stephen’s College Preparatory School. S.P. received education grants, provided consultation, attended advisory board meetings and/or provided lectures for AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, BioInvent, Blueprint Medicines Corporation, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp & Dohme, Merck Serono, Merrimack, Novartis, PharmaMar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda and Vaccibody, from whom she received honoraria (all fees to institution).

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Passaro, A., Jänne, P.A., Mok, T. et al. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat Cancer 2, 377–391 (2021). https://doi.org/10.1038/s43018-021-00195-8

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