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：
10580077
负责人：
Eric Collisson
金额：
$ 40.24万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580077
关键词：
Adenocarcinoma Affinity 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 Epithelium Event Exclusion Exons Fostering Frequencies Gene Mutation Generations 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 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 acquired drug resistance cancer type clinical care crizotinib drug sensitivity druggable target experience gene discovery improved in vivo in vivo Model inhibitor innovation kinase inhibitor malignant breast neoplasm mouse model precision medicine pressure prevent programmed cell death ligand 1 receptor resistance allele 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.

项目概要/摘要摘要：肺癌是最大的癌症杀手，但它也是一种异质性疾病，其中不同的疾病癌蛋白有助于遗传亚型，其中一些亚型尽管具有有利的治疗效果，但仍具有特定的治疗作用。当治疗与驱动癌基因相匹配时，只有一小部分肺癌患者的结果我们的目标是优化大部分肺癌的靶向治疗。携带间充质上皮转化（MET）基因激活突变的患者。背景：MET 突变是最近添加到可药物治疗、经常突变的激酶列表中的。我们最近定义了 NSCLC 中 MET 畸变的频率，并将 MET 近膜域中的外显子 14 缺失确定为最常见的体细胞 MET 事件。然而，其作用机制及其对现有靶向 MET 疗法的敏感性尚不清楚，阻碍对这一大批非小细胞肺癌患者进行针对性治疗。方法：我们将重点关注 MET 外显子 14 突变所带来的信号传导和结构效应，目的是我们首先要了解 NSCLC 中这种突变选择的作用机制。使用纯化的方法表征 MET 近膜片段调节激酶的机制接下来，我们将研究外显子 14 缺失如何影响。 MET 抑制剂的结合以及突变是否赋予特定类别的激酶抑制剂的亲和力。我们将在体内模拟第一代（I 型）MET 抑制剂的耐药突变，并提出策略使用 II 型抑制剂和“off-MET”药物靶点的靶向方法克服这些问题。影响：该项目重点关注肺癌（最致命的癌症）中常见且尚未研究的突变到目前为止，每年有数千名美国人死于 MET 突变肺癌，而且往往没有发生这种情况。正在考虑针对其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 突变的疗法的开发，并优化治疗方法针对最常见的预期抵抗路线。