AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.
AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.
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DOI：
10.1158/2159-8290.cd-14-0337
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发表时间：
2014-09
期刊：
影响因子：
28.2
通讯作者：
Pao W
中科院分区：
文献类型：
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作者：
Cross DA;Ashton SE;Ghiorghiu S;Eberlein C;Nebhan CA;Spitzler PJ;Orme JP;Finlay MR;Ward RA;Mellor MJ;Hughes G;Rahi A;Jacobs VN;Red Brewer M;Ichihara E;Sun J;Jin H;Ballard P;Al-Kadhimi K;Rowlinson R;Klinowska T;Richmond GH;Cantarini M;Kim DW;Ranson MR;Pao W
第一代EGF受体酪氨酸激酶抑制剂(EGFR TKI)为晚期EGFR突变(EGFRm+)非小细胞肺癌(NSCLC)患者提供了显著的临床益处。患者最终会出现疾病进展，通常是由于第二个T790M EGFR TKI耐药突变的获得。AZD9291是一种新型口服、有效和选择性的第三代不可逆抑制物，既可以抑制EGFRm+增敏突变，也可以阻止野生型EGFR产生T790M耐药突变。这种单苯胺嘧啶化合物在结构上不同于其他第三代EGFR TKI，并提供了与早期EGFR TKI不同的药理特征。临床前，该药在体外有效地抑制EGFRm+和EGFRm+/T790M突变细胞株的信号通路和细胞生长，对野生型EGFR细胞株的活性较低，在EGFR突变肿瘤异种移植和转基因模型中转化为深度和持续的肿瘤消退。两名晚期EGFRm T790M+NSCLC患者的治疗被描述为原则证明。
First generation EGF receptor tyrosine kinase inhibitors (EGFR TKIs) provide significant clinical benefit in patients with advanced EGFR mutant (EGFRm+) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent and selective third generation irreversible inhibitor of both EGFRm+ sensitizing and T790M resistance mutants that spares wild-type EGFR. This monoanilino-pyrimidine compound is structurally distinct from other third generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Pre-clinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm+ and EGFRm+/T790M mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR mutant tumor xenograft and transgenic models. The treatment of two patients with advanced EGFRm T790M+ NSCLC is described as proof of principle.