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Project 2: Mechanism-based approaches to counter TKI resistance in EGFR mutant lung cancer

项目2：基于机制的方法对抗EGFR突变肺癌中的TKI耐药

基本信息

批准号：
10203855
负责人：
KATERINA Abigail POLITI
金额：
$ 38.55万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-26 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10203855
关键词：
Address Adoption Antibodies Automobile Driving Binding Biochemical Biochemistry Cancer Biology Clinic Clinical DNA Sequence Alteration Data Development Diagnosis Dimerization Epidermal Growth Factor Receptor Epigenetic Process Erlotinib Exons Family member Frequencies Gefitinib Gene Expression Profile Generations Genes Genotype Heterodimerization Homo In Vitro Knowledge Lung Adenocarcinoma Malignant neoplasm of lung Mediating Modeling Molecular Mutate Mutation Nature Oncogenic Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacology Pre-Clinical Model Progression-Free Survivals Property Resistance Resources Role SMARCA4 gene Speed Structure Testing Therapeutic Therapeutic Studies Toxic effect Tyrosine Kinase Domain Tyrosine Kinase Inhibitor Variant acquired drug resistance base biochemical tools chromatin remodeling genomic tools improved outcome in vivo Model innovation insight mouse model mutant novel therapeutics patient response patient subsets personalized medicine receptor resistance mechanism resistance mutation structural biology success targeted treatment treatment strategy tumor tumor progression

项目摘要

PROJECT SUMMARY Targeted therapies have completely transformed the landscape for diagnosis and treatment of metastatic lung cancer. Despite this success, targeted therapies are not curative and acquired resistance is a major impediment to cures or durable responses for patients treated with these therapies. A paradigm for the success of targeted therapies in lung cancer, comes from Epidermal Growth Factor Receptor (EGFR) mutant lung cancer. Mutations in exons encoding the tyrosine kinase domain of EGFR are found in approximately 10- 15% of lung adenocarcinomas in the US. These mutations confer sensitivity to tyrosine kinase inhibitors (TKIs) and four TKIs (erlotinib, gefitinib, afatinib and, most recently, osimertinib) are currently approved for the first-line treatment of EGFR mutant lung cancer. Acquired drug resistance, however, is a major challenge with all of these TKIs including osimertinib, but we have very limited knowledge of the mechanisms of resistance to osimertinib given its recent adoption in the clinic. Without knowledge about resistance mechanisms, optimal post-osimertinib treatment strategies remain to be defined. Data from our labs and others indicate that osimertinib resistance can arise through both EGFR-dependent mechanisms involving several different types of EGFR mutation and EGFR-independent mechanisms – frequently epigenetic in origin – that are poorly understood. Very little is known about the molecular context(s) in which these resistance mechanisms emerge, their frequency, biochemistry and how to target them pharmacologically. Given the speed of adoption of osimertinib as 1st line therapy, there is an urgent need to identify these mechanisms and resulting vulnerabilities. We propose to leverage our collective expertise in lung cancer biology, mouse models, resistance to targeted therapies and EGFR structural biology to address these issues. Using unique in vitro and in vivo models and patient resources of acquired resistance to osimertinib, innovative genomic and biochemical tools we will: 1) Identify molecular features and new therapeutic vulnerabilities of osimertinib-resistance EGFR variants. 2) Establish mutant EGFR heterodimerization patterns and determine whether these can be leveraged therapeutically to overcome osimertinib resistance; 3) Identify epigenetic processes that confer TKI resistance. Our studies will yield a comprehensive understanding of osimertinib resistance and insight with which to develop new mechanism-based approaches to target osimertinib-resistant tumors – an urgent unmet clinical need.

项目总结