Mechanisms of acquired resistance to first-and second-generation EGFR tyrosine kinase inhibitors

D. Westover, J. Zugazagoitia, B. C. Cho, C. M. Lovly, L. Paz-Ares

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321 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)i10-i19
JournalAnnals of Oncology
Publication statusPublished - 2018 Jan 1

Bibliographical note

Funding Information:
DW was supported by a Ruth L. Kirschstein NRSA Fellowship (T32HL094296). JZ was funded by Instituto de Salud Carlos III (Rio Hortega, CM15/00196). BCC was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2016R1A2B3016282). CML received support from the National Institutes of Health (NIH) and National Cancer Institute (NCI) R01CA121210 and P01-CA129243. CML was also supported by a Damon Runyon Clinical Investigator Award, a LUNGevity Career Development Award, a V Foundation Scholar-in-Training Award, an AACR-Genentech Career Development Award, and U10CA180864. LPA was funded by ISCIII: PI1401964, PIE15/ 00076, RTICC (R12/0036/0028) and CIBERONC (C16/12/ 00442), co-funded by FEDER from Regional Development European Funds (European Union) (no grant number applies).

Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology


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