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.

表皮生长因子受体 ( EGFR)基因的外显子 20 中三个或更多碱基对的框内插入是首批被确定为非小细胞肺癌 (NSCLC) 致癌驱动因素的EGFR突变之一。然而，与代表 NSCLC 中大多数EGFR突变的经典EGFR L858R 点突变或外显子 19 缺失不同，低频EGFR外显子 20 插入突变与靶向 EGFR 抑制剂的从头耐药性相关，并与患者不良预后相关。在这里，我们回顾了过去 5 年的进展，其中临床前研究（包括阐明 EGFR 外显子 20 插入突变激酶的晶体结构）揭示了激酶激活和空间构象的独特机制，这些机制定义了缺乏反应这些EGFR突变为临床批准的 EGFR 抑制剂。最近开发的几种选择性抑制EGFR外显子 20 插入的新型小分子化合物为未来的治疗选择带来了希望，这些治疗选择将对患有这种分子亚型 NSCLC 的患者有效。