Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping.
Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping.
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DOI：
10.1158/2159-8290.cd-14-1467
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发表时间：
2015-08
期刊：
影响因子：
28.2
通讯作者：
Ladanyi M
中科院分区：
文献类型：
--
作者：
Paik PK;Drilon A;Fan PD;Yu H;Rekhtman N;Ginsberg MS;Borsu L;Schultz N;Berger MF;Rudin CM;Ladanyi M
MET外显子14 RNA剪接受体和供体位点中的突变导致外显子跳跃、含有Cbl E3-泛素连接酶结合位点的跨膜结构域的缺失以及所得异常MET蛋白的转换减少，先前报道在临床前模型中是致癌的。我们现在报告了4例IV期肺腺癌患者对MET抑制剂克唑替尼和卡博替尼的反应，这些患者携带导致MET外显子14跳跃的突变，突出了4%肺腺癌患者的新治疗策略，这些患者的肿瘤携带这种以前未被充分认识的遗传改变。
Mutations in the MET exon 14 RNA splice acceptor and donor sites, which lead to exon skipping, deletion of the juxtamembrane domain containing the Cbl E3-ubiquitin ligase binding site, and decreased turnover of the resultant aberrant MET protein, were previously reported to be oncogenic in preclinical models. We now report responses to the MET inhibitors crizotinib and cabozantinib in four patients with stage IV lung adenocarcinomas harboring mutations leading to MET exon 14 skipping, highlighting a new therapeutic strategy for the 4% of lung adenocarcinoma patients whose tumors harbor this previously underappreciated genetic alteration.