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Optimizing Treatment Approaches to Lung Cancers Harboring MET Exon 14 mutations

优化含有 MET 外显子 14 突变的肺癌的治疗方法

基本信息

批准号：
9891979
负责人：
Eric Collisson
金额：
$ 44.51万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891979
关键词：
Active Sites Address Adenocarcinoma Affect Affinity American Animals Automobile Driving Binding Biological Cancer Etiology Cancer Patient Cells Clinic Clinical Colon Carcinoma Coupled Custom Disease Drug resistance Epidermal Growth Factor Receptor Epithelial Epithelial Cells Epithelium Event Exons Fostering Frequencies Gene Mutation Generations Genes Genetic Genotype Goals Grant Human Immunocompetent Immunotherapy In Vitro KRAS2 gene Lead Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Medical Oncologist Mesenchymal Methods Minority Missense Mutation Modeling Mutagenesis Mutate Mutation Non-Small-Cell Lung Carcinoma Oncogenes Oncoproteins Outcome Pathway interactions Patients Phosphotransferases Play Population Predisposition Recurrence Reporting Research Resistance Resistance development Role Route Signal Transduction Structure The Cancer Genome Atlas Therapeutic Therapeutic Trials Time Ursidae Family airway epithelium base cancer type crizotinib drug sensitivity druggable target in vivo inhibitor/antagonist innovation kinase inhibitor malignant breast neoplasm mouse model mutation screening novel personalized medicine prevent resistance mechanism resistance mutation response screening structural biology success targeted treatment therapy development treatment optimization tumor

项目摘要

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.

肺癌是最大的癌症杀手，但也是一种异质性疾病，癌蛋白有助于基因亚型，其中一些携带特定的治疗。尽管有利当治疗与驱动癌基因相匹配时，只有一小部分肺癌患者以有针对性的方式对待。我们的目标是优化大比例肺癌的靶向治疗间充质上皮转化（MET）基因中携带激活突变的患者。背景：MET突变是最近加入到可药物化的、反复突变的激酶列表中的，非小细胞肺癌（NSCLC）。我们最近确定了NSCLC中MET畸变的频率，并且鉴定MET的质膜结构域中的外显子14缺失为最常见的体细胞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，阻止对这一庞大的NSCLC患者群体进行靶向治疗。方法：我们将关注MET外显子14突变可能对激酶产生的多种影响，目标是了解这种突变如何导致癌症。我们将首先描述MET的质膜部分，调节激酶。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，以及是否突变赋予对特定种类的激酶抑制剂的亲和力。最后，我们将模拟原型阻力突变的第一代（I型）MET抑制剂在体内，并建议策略，以克服他们使用 II型抑制剂的靶向方法。影响：该项目的重点是肺癌中一种常见且未充分研究的突变，肺癌是最致命的癌症。类型，到目前为止。每年有成千上万的美国人死于MET突变的肺癌，而且通常没有正在考虑针对他们的肿瘤基因型进行靶向治疗。我们将阐明MET突变的作用在肺癌中起作用，并将在结构上定义最常见的突变如何激活这种癌蛋白。该项目将促进靶向MET外显子14突变的疗法的开发，并优化方法，针对最常见的预期抵抗路线。