Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors
Open accessAbstract
Patients with non-small-cell lung cancer (NSCLC) whose tumours harbour activating mutations within the epidermal growth factor receptor (EGFR) frequently derive significant clinical and radiographic benefits from treatment with EGFR tyrosine kinase inhibitors (TKIs). As such, prospective identification of EGFR mutations is now the standard of care worldwide. However, acquired therapeutic resistance to these agents invariably develops. Over the past 10 years, great strides have been made in defining the molecular mechanisms of EGFR TKI resistance in an effort to design rational strategies to overcome this acquired drug resistance. Approximately 60% of patients with acquired resistance to the EGFR TKIs (erlotinib, gefitinib, and afatinib) develop a new mutation within the drug target. This mutation-T790M-has been shown to alter drug binding and enzymatic activity of the mutant EGF receptor. Less common mechanisms of acquired resistance include MET amplification, ERBB2 amplification, transformation to small-cell lung cancer, and others. Here, we present a condensed overview of the literature on EGFR-mutant NSCLC, paying particular attention to mechanisms of drug resistance, recent clinical trial results, and novel strategies for identifying and confronting drug resistance, while also striving to identify gaps in current knowledge. These advances are rapidly altering the treatment landscape for EGFR-mutant NSCLC, expanding the armamentarium of available therapies to maximize patient benefit.
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MET amplification has been shown to co-exist with the T790M mutation.
“MET amplification has also been shown to co-exist with the T790M mutation”
From Afatinib for the treatment of <i>EGFR</i> mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [95]
In tumors with MET amplification, the use of MET inhibitors together with EGFR TKIs has shown preliminary efficacy.
“In tumors with MET amplification, the use of MET inhibitors together with EGFR TKIs has shown preliminary efficacy.”
From Afatinib for the treatment of <i>EGFR</i> mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [95]
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HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence
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- Authors
- Westover, D., Zugazagoitia, J., Cho, B. C., Lovly, C. M., & Paz-Ares, L.
- Affiliations
- Vanderbilt University Medical Center (US)
- Research Institute Hospital 12 de Octubre (ES)
- Yonsei University (KR)
- Vanderbilt-Ingram Cancer Center (US)
- Universidad Complutense de Madrid (ES)
- Corresponding author
- Lovly, C.M.
- Paz-Ares, L.
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 29
- Issue
- suppl_1
- Pages
- i10-i19
- ISSN
- 0923-7534 (ISSN-L)
- PMC
- PMC6454547
- OpenAlex
- W2792821195
- Cited by
- 766
- References
- 27
- Citations by year
- 2026: 81 · 2025: 94 · 2024: 114 · 2023: 127 · 2022: 115 · 2021: 99 · 2020: 69 · 2019: 55 · 2018: 11
- FWCI
- 10.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Instituto de Salud Carlos III (CM15/00196)
- National Research Foundation of Korea
- NRF
- National Institutes of Health (NIH)
- National Cancer Institute
- NCI (R01CA121210 and P01-CA129243)
- ISCIII (PI1401964, PIE15/00076)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- EGFR tyrosine kinase inhibitors, acquired drug resistance, EGFR-mutant non-small cell lung cancer, T790M mutation, erlotinib, gefitinib, afatinib, MET amplification, ERBB2 amplification, small cell lung cancer transformation, resistance mechanisms, targeted therapy
- MeSH terms
- Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Cell Transformation, Neoplastic, Humans, Lung Neoplasms, Mutation, Randomized Controlled Trials as Topic, Treatment Outcome, Erb-b2 Receptor Tyrosine Kinases, Receptor, ErbB-2, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-met, Protein Kinase Inhibitors, Small Cell Lung Carcinoma, ErbB Receptors
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