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Review
. 2018 Jan 1;29(suppl_1):i10-i19.
doi: 10.1093/annonc/mdx703.

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

D Westover  1 , J Zugazagoitia  2   3   4   5 , B C Cho  6 , C M Lovly  1   7   8 , L Paz-Ares  2   3   4   5   9
Affiliations
Review

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

D Westover et al. Ann Oncol. .

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.

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Figures

Figure 1.
Figure 1.
Mechanisms of acquired resistance to first- and second-generation EGFR TKIs. Frequencies (given in parentheses) are approximations. Only mechanisms that have been detected in patients and reported in at least two independent data series are included.
Figure 2.
Figure 2.
Proposed algorithm for the management and treatment of non-central nervous system progression. Red text refers to standard treatment options. CNS, central nervous system; TKI: tyrosine kinase inhibitor.
Figure 3.
Figure 3.
Proposed algorithm for the management and treatment of isolated central nervous system progression. Red text refers to standard treatment options. CNS, central nervous system; WBRT, whole brain radiotherapy; TKI, tyrosine kinase inhibitor.
See this image and copyright information in PMC

References

    1. Lynch TJ, Bell DW, Sordella R. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib. N Engl J Med 2004; 350(21): 2129–2139. - PubMed
    1. Paez JG, Jänne PA, Lee JC. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304(5676): 1497–1500. - PubMed
    1. Pao W, Miller V, Zakowski M. et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004; 101(36): 13306–13311. - PMC - PubMed
    1. Rosell R, Moran T, Queralt C. et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361(10): 958–967. - PubMed
    1. Yatabe Y, Kerr KM, Utomo A. et al. EGFR mutation testing practices within the Asia Pacific region: results of a multicenter diagnostic survey. J Thorac Oncol 2015; 10(3): 438–445. - PMC - PubMed

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