Targeting <i>EGFR</i> exon 20 insertion mutations in non-small cell lung cancer.
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Inframe insertions of three or more base pairs in exon 20 of the epidermal growth factor receptor (<i>EGFR)</i> gene were among the first <i>EGFR</i> mutations to be identified as oncogenic drivers in non-small cell lung cancer (NSCLC). However, unlike the classical <i>EGFR</i> L858R point mutation or exon 19 deletions, which represent the majority of <i>EGFR</i> mutations in NSCLC, low frequency <i>EGFR</i> exon 20 insertion mutations are associated with de novo resistance to targeted EGFR inhibitors and correlate with a poor patient prognosis. Here, we review the developments over the last 5 years in which pre-clinical studies, including elucidation of the crystal structure of an EGFR exon 20 insertion mutant kinase, have revealed a unique mechanism of kinase activation and steric conformation that define the lack of response of these <i>EGFR</i> mutations to clinically approved EGFR inhibitors. The recent development of several novel small molecule compounds that selectively inhibit <i>EGFR</i> exon 20 insertions holds promise for future therapeutic options that will be effective for patients with this molecular subtype of NSCLC.
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Molecular and Systems Oncology
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Signal transduction and targeted therapy, 2019, 4 pp. 5 - ?