The structural and functional basis of MET exon 14 activation and acquired drug resistance

MET 外显子 14 激活和获得性耐药的结构和功能基础

基本信息

批准号：
9892984
负责人：
Eric Collisson
金额：
$ 40.99万
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/9892984
关键词：
Adenocarcinoma Affinity Alleles American Animals Automobile Driving Binding Biological Biology Cancer Etiology Cancer Patient Cells Clinical Colon Carcinoma Development Disease Drug Modelings Drug Targeting Epidermal Growth Factor Receptor Epithelial Epithelium Event Exons Fostering Frequencies Gene Mutation Generations Genes Genetic Genomics Genotype Goals Grant Immunotherapy In Vitro Knowledge Lead Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Medical Oncologist Mesenchymal Methods Missense Mutation Modeling Molecular Conformation Mutate Mutation Non-Small-Cell Lung Carcinoma Oncogenes Oncoproteins Outcome Patients Pharmaceutical Preparations Phosphotransferases Plant Roots Play Population Predisposition Protein Analysis Protein Kinase Publishing Receptor Protein-Tyrosine Kinases Receptor Signaling Recombinants Recurrence Research Resistance Role Route Signal Transduction Structure Testing The Cancer Genome Atlas Time acquired drug resistance cancer type clinical care crizotinib drug sensitivity druggable target experience gene discovery improved in vivo in vivo Model inhibitor/antagonist innovation kinase inhibitor malignant breast neoplasm mouse model precision medicine pressure prevent programmed cell death ligand 1 receptor resistance mechanism resistance mutation response targeted treatment therapeutic development therapy development tumor

项目摘要

Project Summary/Abstract Summary: 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 manner. 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 signaling and structural effects MET exon 14 mutations impart with the goal of understanding the mechanism of action underlying selection for this mutation in NSCLC. We will first characterize the mechanism by which the juxtamembrane segment of MET regulates the kinase, using purified recombinant MET fragments from its intracellular domain. Next, we will study how exon 14 deletions influence MET inhibitors' binding and whether mutation confers affinity for specific classes of kinase inhibitors. Finally, we will model resistance mutations to first generation (Type I) MET inhibitors in vivo, and suggest strategies to overcome them using targeted approaches with Type II inhibitors and “off-MET” drug targets. 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.

项目摘要/摘要摘要：肺癌是最大的癌症杀手，但也是一种异质疾病，其中不同癌蛋白有助于遗传亚型，其中一些含有特定的治疗方法。尽管有利当疗法与驱动癌基因相匹配时，只有一小部分肺癌患者是以目标方式进行处理。我们的目标是优化针对大部分肺癌的靶向疗法在间质上皮转化（MET）基因中具有激活突变的患者。背景：MET突变是在可吸毒，复发性突变激酶列表中的最新补充非小细胞肺癌（NSCLC）。我们最近定义了NSCLC中MET像差的频率，并确定了MET的近去膜域中的外显子14删除是最常见的体细MET事件。但是，其作用的机制及其对现有靶向MET疗法的敏感性的定义很差，防止针对这一大量NSCLC患者的有针对性治疗。方法：我们将专注于信号传导和结构效应符合外显子14突变的目标了解NSCLC中该突变的基础选择的作用机理。我们将首先表征MET的置膜段调节激酶的机制，并使用纯化重组符合其细胞内结构域的碎片。接下来，我们将研究外显子14删除如何影响 MET抑制剂的结合以及突变自白是否对特定类别的激酶抑制剂的亲和力。最后，我们将对第一代（I型）符合体内抑制剂的抗性突变进行建模，并提出策略使用具有II型抑制剂和“脱水”药物靶标的目标方法来克服它们。影响：该项目着重于肺癌的常见和理解的突变，这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遇到的肺癌，并且经常没有这样做被考虑针对其肿瘤基因型的靶向治疗。我们将阐明角色遇到的突变在肺癌中发挥作用，并将在结构上定义最常见的突变如何激活这种癌蛋白。该项目将促进针对靶向外显子14突变的疗法的开发，并优化方法针对最常见的阻力途径。