Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer.
Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer.
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DOI：
10.1158/2159-8290.cd-16-0686
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发表时间：
2016-12
期刊：
影响因子：
28.2
通讯作者：
Oxnard GR
中科院分区：
文献类型：
--
作者：
Bahcall M;Sim T;Paweletz CP;Patel JD;Alden RS;Kuang Y;Sacher AG;Kim ND;Lydon CA;Awad MM;Jaklitsch MT;Sholl LM;Jänne PA;Oxnard GR
扩增和/或突变的 MET 在非小细胞肺癌 (NSCLC) 中既可以作为主要致癌驱动因素，也可以作为酪氨酸激酶抑制剂 (TKI) 耐药性的促进剂。然而，MET 特异性靶向药物的前景仍然不发达，对 MET TKI 耐药机制的了解也很有限。在这里，我们介绍了一名患有 EGFR 突变和 MET 扩增的肺腺癌患者的病例，该患者在接受厄洛替尼治疗后出现进展，对沃利替尼和奥希替尼联合 MET 和 EGFR 抑制反应显着。当对该组合产生耐药性时，检测到新的 MET 激酶结构域突变 D1228V。我们的体外研究结果表明，MET D1228V 通过受损的药物结合诱导对 I 型 MET TKI 的耐药性，同时保持对 II 型 MET TKI 的敏感性。基于这些发现，该患者接受了厄洛替尼联合卡博替尼（一种 II 型 MET 抑制剂）治疗，并表现出缓解。
Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped and understanding of mechanisms of resistance to MET TKIs is limited. Here we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib, responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib. When resistance developed to this combination, a new MET kinase domain mutation, D1228V, was detected. Our in vitro findings demonstrate that MET D1228V induces resistance to type I MET TKIs through impaired drug binding while sensitivity to type II MET TKIs is maintained. Based on these findings, the patient was treated with erlotinib combined with cabozantinib, a type II MET inhibitor, and exhibited a response.