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Mechanisms and Vulnerabilities of SWI/SNF chromatin remodeling complex mutant lung cancer

SWI/SNF染色质重塑复合体突变型肺癌的机制和脆弱性

基本信息

批准号：
10207560
负责人：
Yonathan Lissanu
金额：
$ 47.2万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10207560
关键词：
ARID1A gene Biogenesis Biological Biological Models CRISPR/Cas technology Cancer Etiology Cancer cell line Catalytic Domain Cells Cellular Metabolic Process Chemicals Chromatin Chromatin Remodeling Factor Clinic Clinical Clinical Research Complex Custom Data Dependence Development Disease Drug Combinations Drug Targeting Epidermal Growth Factor Receptor FDA approved Foundations Frequencies Future Gene Expression Gene Targeting Genes Genetic Screening Genetic Transcription Genetically Engineered Mouse Genomics Goals Growth Guide RNA Immunotherapy Knock-out Libraries LoxP-flanked allele Lung Neoplasms Maintenance Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic Metabolism Mitochondria Modeling Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Oxidative Phosphorylation Oxygen Oxygen Consumption Patients Pharmaceutical Preparations Positioning Attribute Process Publishing Role SMARCA2 gene SMARCA4 gene Screening Result Stress Sucrose TP53 gene Therapeutic Therapeutic Studies Translating Tumor Suppressor Proteins Work Xenograft procedure cancer cell cancer subtypes clinical development clinically relevant design efficacy testing gene product improved in vivo inhibitor/antagonist insight lung cancer cell metabolomics mortality mouse model mutant novel novel therapeutics patient derived xenograft model pre-clinical programmed cell death ligand 1 response small molecule targeted treatment therapeutically effective tool treatment strategy tumor tumor growth tumor microenvironment tumor xenograft

项目摘要

Project Summary Lung cancer is a devastating disease that remains the top cause of cancer mortality. Despite recent advances, the majority of patients with lung cancer lack effective therapeutic options, underscoring the dire need for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. We recently demonstrated that Smarca4 acts as a bona fide tumor suppressor in mice and cooperates with p53 loss and Kras activation. Importantly, SMARCA4 mutant cancer cells have heightened sensitivity to inhibition of oxidative phosphorylation (OXPHOS) by a novel small molecule, IACS-10759. Mechanistically, we showed that SMARCA4-deficient cells have a blunted transcriptional response to energy stress creating a therapeutically relevant vulnerability. Taking these observations together, we hypothesize that OXPHOS inhibition using IACS-10759 is an attractive therapeutic strategy for lung cancers with mutations in the SWI/SNF complex. The major objectives of the proposed study are to discover the mechanistic basis of the metabolic rewiring in SWI/SNF mutants and provide preclinical evidence to guide future clinical study of IACS-10759 in patients with SWI/SNF mutant lung cancer. Due to the unique microenvironment of lung cancer including high local oxygen tension, it is imperative to study therapeutic agents targeting metabolism orthotopically. Hence, we will test efficacy of IACS-10759 in GEM models of lung cancer. Further, PDX models have emerged as powerful tools to help guide treatment strategies. Thus, we propose to determine the potential of OXPHOS inhibition in various SWI/SNF mutant PDX model systems. While our preliminary data indicates that IACS-10759 treatment leads to tumor growth inhibition, synergistic combination strategies are expected to be even superior in efficacy. Thus, we propose to identify optimal combination agents that synergize with IACS-10759 by using a chemo-genetic screen. Here, we will use CRISPR-Cas9 and a custom designed library of guide RNAs against genes targeted by FDA approved drugs (FDAome). We will validate the results of the screen by performing one-on-one drug combination studies in vivo. Finally, our preliminary data suggests that SMARCA2 is required for expression of PGC1α, a master transcriptional regulator of mitochondrial biogenesis and OXPHOS, in SMARCA4 mutant cells. We know from our published work that PGC1α is essential in SMARCA4 deficient cells. Thus we hypothesize that SMARCA2 is a survival factor and a major driver of metabolic rewiring in SMARCA4 deficient cells in a PGC1α dependent manner. In conclusion, our study is expected to provide mechanistic insight into the metabolic dysregulation of SWI/SNF mutant lung cancers and lay the foundation for future clinical development of the OXPHOS inhibitors as therapeutics.

项目总结