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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.

项目总结/文摘