奥西默替尼
表皮生长因子受体
表皮生长因子受体抑制剂
点突变
癌症研究
突变
肺癌
癌症
医学
生物
埃罗替尼
肿瘤科
内科学
基因
遗传学
作者
Laura Scalvini,Riccardo Castelli,Silvia La Monica,Marcello Tiseo,Roberta Alfieri
标识
DOI:10.1016/j.bcp.2021.114643
摘要
Third-generation inhibitors of the epidermal growth factor receptor (EGFR), best exemplified by osimertinib, have been developed to selectively target variants of EGFR bearing activating mutations and the mutation of gatekeeper T790 in patients with EGFR-mutated forms of Non-Small Cell Lung Cancer (NSCLC). While the application of third-generation inhibitors has represented an effective first- and second-line treatment, the efficacy of this class of inhibitors has been hampered by the novel, tertiary mutation C797S, which may occur after the treatment with osimertinib. More recently, other point mutations, including L718Q, G796D, G724S, L792 and G719, have emerged as mutations mediating resistance to third-generation inhibitors. The challenge of overcoming newly developed and recurrent resistances mediated by EGFR-mutations is thus driving the search of alternative strategies in the design of new therapeutic agents able to block EGFR-driven tumor growth. In this manuscript we review the recently emerged EGFR-dependent mechanisms of resistance to third-generation inhibitors, and the achievements lately obtained in the development of next-generation EGFR inhibitors.
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