外显子
表皮生长因子受体
癌症研究
点突变
肺癌
生物
突变
突变体
医学
基因
分子生物学
癌症
T790米
遗传学
吉非替尼
病理
作者
Simon Vyse,Paul H. Huang
标识
DOI:10.1038/s41392-019-0038-9
摘要
Abstract Inframe insertions of three or more base pairs in exon 20 of the epidermal growth factor receptor ( EGFR) gene were among the first EGFR mutations to be identified as oncogenic drivers in non-small cell lung cancer (NSCLC). However, unlike the classical EGFR L858R point mutation or exon 19 deletions, which represent the majority of EGFR mutations in NSCLC, low frequency EGFR 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 EGFR mutations to clinically approved EGFR inhibitors. The recent development of several novel small molecule compounds that selectively inhibit EGFR 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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