MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma.
MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma.
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DOI：
10.1158/0008-5472.can-16-1944
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发表时间：
2017-08-15
期刊：
影响因子：
11.2
通讯作者：
Collisson EA
中科院分区：
文献类型：
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作者：
Lu X;Peled N;Greer J;Wu W;Choi P;Berger AH;Wong S;Jen KY;Seo Y;Hann B;Brooks A;Meyerson M;Collisson EA
靶向体细胞激活的癌基因已经彻底改变了非小细胞肺癌（NSCLC）的治疗。外显子14剪接位点附近的基因间充质-上皮转化（MET）突变在肺腺癌中复发，并导致外显子跳跃（METΔ14）。在这里，我们分析了来自12种不同恶性肿瘤的4，422个样本，以估计所述外显子跳跃的速率。METΔ14突变和转录本在肺腺癌中最常见。METΔ14以肝细胞生长因子（HGF）依赖性方式转化人肺上皮细胞的内源性表达水平。此外，在一种新的免疫活性小鼠模型中，orthopathy小鼠等位基因的过表达诱导了肺腺癌。Met抑制在该模型中显示出临床益处。此外，我们在1例METΔ14驱动的NSCLC患者中观察到克唑替尼的临床应答，仅在临床进展时观察到MET激活环中的新错义突变，这对与克唑替尼结合至关重要。这些发现支持在一部分NSCLC患者中针对METΔ14的基因组选择的临床试验，证实了在获得性耐药之前和之后进一步治疗靶向的第二位点突变，并为在免疫活性宿主中研究METΔ14提供了体内系统。
Targeting somatically activated oncogenes has revolutionized the treatment of non-small cell lung cancer (NSCLC). Mutations in the gene mesenchymal-epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a Hepatocyte growth factor (HGF)-dependent manner. Additionally, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. Additionally, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed towards METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host.