Optimizing Treatment Approaches to Lung Cancers Harboring MET Exon 14 mutations

肺癌是最大的癌症杀手，但也是一种不同类型的疾病 癌蛋白对遗传亚型有贡献，其中一些亚型具有特定的治疗方法。尽管是有利的 结果当治疗与致癌基因匹配时，只有一小部分肺癌患者的治疗结果与癌基因匹配 以有针对性的方式对待。我们的目标是优化很大比例肺癌的靶向治疗 存在间充质上皮转化(MET)基因激活突变的患者。 背景：MET突变是最新增加的可用药、反复突变的激酶 非小细胞肺癌(NSCLC)。我们最近定义了非小细胞肺癌中MET像差的频率， MET膜旁区域14号外显子缺失是最常见的体细胞MET事件。 然而，其作用机制及其对现有靶向MET疗法的敏感性尚不明确， 阻止对这一大群非小细胞肺癌患者进行有针对性的治疗。 方法：我们将重点研究MET外显子14突变可能对激酶的多种影响，目的是 了解这种突变是如何导致癌症的。我们将首先描述MET的膜旁节段。 调节着这一激酶。接下来，我们将研究外显子14缺失如何影响MET抑制剂的结合，以及是否 突变使特定类别的激酶抑制剂具有亲和力。最后，我们将模拟原型阻力 突变到第一代(I型)在体内遇到抑制剂，并提出克服它们的策略 使用II型抑制剂的靶向方法。 影响：这个项目关注的是肺癌中一种常见且未被充分研究的突变，肺癌是最致命的癌症 打字，到目前为止。每年有数以千计的美国人死于MET突变的肺癌，而且往往是在没有MET突变的情况下 正在考虑针对他们的肿瘤基因进行靶向治疗。我们将澄清MET突变的角色 在肺癌中发挥作用，并将在结构上定义最常见的突变如何激活这种癌蛋白。 该项目将促进针对MET外显子14突变的治疗方法的开发，并优化方法以 目标是最常见的预期抵抗路线。

Lung cancer is the largest cancer killer but is also a heterogeneous disease in which different oncoproteins contribute to genetic subtypes, some of which carry specific treatments. Despite favorable outcomes when therapies are matched to driving oncogenes, only small fraction of lung cancer patients are treated in a targeted manners. Our goal is to optimize targeted therapy for the large proportion of lung cancer patients harboring activating mutations in the Mesenchymal Epithelial Transformation (MET) gene. Background: MET mutations are the most recent addition to the list of druggable, recurrently mutated kinases in nonsmall cell lung cancer (NSCLC). We have recently defined the frequency of MET aberrations in NSCLC, and identified exon 14 deletion in the juxtamembrane domain of MET as the most common somatic MET event. The mechanism for its action and its susceptibility to existing targeted MET therapies is however poorly defined, preventing targeted treatment of this large population of NSCLC patients. Methods: We will focus on the many effects MET exon 14 mutations may have on the kinase, with the goal of understanding how this mutation drives cancer. We will first characterize the juxtamembrane segment of MET regulates the kinase. Next, we will study how exon 14 deletions affect MET inhibitors' binding and whether mutation confers affinity for specific classes of kinase inhibitors. Finally, we will model prototypical resistance mutations to first generation (Type I) MET inhibitors in vivo, and suggest strategies to overcome them using targeted approaches with Type II inhibitors. Impact: This project focuses on a common and understudied mutation in lung cancer, the most lethal cancer type, by far. Thousands of Americans die each year with MET-mutated lung cancer, and often do so without being considered for targeted therapy against their tumor's genotype. We will clarify the role MET mutation plays in lung cancer and will structurally define how the most common mutations activate this oncoprotein. This project will foster development of therapies targeting MET exon 14 mutations, and optimize approaches to targeting the most common anticipated routes of resistance.