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

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

Research output: Contribution to journalReview article

37 Citations (Scopus)

Abstract

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
Volume29
DOIs
Publication statusPublished - 2018 Jan 1

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Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Drug Resistance
Non-Small Cell Lung Carcinoma
Mutation
Small Cell Lung Carcinoma
Therapeutics
Standard of Care
Pharmaceutical Preparations
Clinical Trials
Neoplasms

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

Cite this

Westover, D. ; Zugazagoitia, J. ; Cho, ByoungChul ; Lovly, C. M. ; Paz-Ares, L. / Mechanisms of acquired resistance to first-and second-generation EGFR tyrosine kinase inhibitors. In: Annals of Oncology. 2018 ; Vol. 29. pp. i10-i19.
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Mechanisms of acquired resistance to first-and second-generation EGFR tyrosine kinase inhibitors. / Westover, D.; Zugazagoitia, J.; Cho, ByoungChul; Lovly, C. M.; Paz-Ares, L.

In: Annals of Oncology, Vol. 29, 01.01.2018, p. i10-i19.

Research output: Contribution to journalReview article

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