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Review
. 2017 Oct 9:8:147-159.
doi: 10.2147/LCTT.S117944. eCollection 2017.

EGFR T790M: revealing the secrets of a gatekeeper

Brian Ko  1 , Daniel Paucar  1 , Balazs Halmos  1
Affiliations
Review

EGFR T790M: revealing the secrets of a gatekeeper

Brian Ko et al. Lung Cancer (Auckl). .

Abstract

Non-small-cell lung cancers that harbor activating mutations in the EGFR gene represent an important molecularly defined subset of lung cancer. Despite dramatic initial responses with first- and second-generation EGFR-directed tyrosine-kinase inhibitors (TKIs) against these cancers, the development of a dominant and frequent resistance mechanism through a threonine-methionine amino acid substitution at position 790 (T790M) of EGFR has limited the long-term efficacy of these targeted therapies. This "gatekeeper" EGFR T790M alteration remains the only validated and relevant second-site resistance mutation for EGFR, allowing for focused research to understand and overcome EGFR T790M-mediated resistance. The current review focuses on EGFR T790M by discussing mechanisms of resistance mediated by EGFR T790M, reviewing development of novel third-generation EGFR TKIs targeting EGFR T790M, and highlighting current research on overcoming resistance to third-generation EGFR T790M TKIs.

Keywords: T790M; epidermal growth factor receptor; lung cancer; resistance; targeted therapy.

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Conflict of interest statement

Disclosure BH has received consulting fees from Foundation One, Genoptix, Boehringer-Ingelheim, Takeda, Novartis, Astra-Zeneca, Genentech, Pfizer, and Eli-Lilly, and research support from Merck, Bristol-Myers-Squibb, Pfizer, Mirati, Takeda, AstraZeneca, Boehringer-Ingelheim, Novartis, Eli-Lilly, and Genentech. The other authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Molecular targets of EGFR inhibitors (A); exon map of EGFR mutations (B). Abbreviation: TKI, tyrosine-kinase inhibitor.
Figure 2
Figure 2
Flowchart for management of advanced NSCLC. Abbreviations: NSCLC, non-small-cell lung cancer; SCLC, small cell lung cancer; SC, small cell; TKI, tyrosine-kinase inhibitor.
See this image and copyright information in PMC

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References

    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. 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. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–957. - PubMed
    1. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380–2388. - PubMed
    1. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239–246. - PubMed