Targeting SMARCA2 as a therapeutic strategy in SMARCA4 mutant lung cancer

点击翻译按钮获取中文摘要

Project Summary Lung cancer is 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. Recent reports and our own data have identified the paralogue SMARCA2 to be synthetic lethal to SMARCA4. However, identifying selective inhibitors of SMARCA2 has been challenging. Hence, we have developed novel SMARCA2 degrading small molecules based on the proteolysis targeting chimera (PROTAC) technology. We demonstrated that YD23, our lead SMARCA2 PROTAC, potently and selectively induces degradation of SMARCA2. We further showed that YD23 selectively inhibits growth of SMARCA4 mutant lung cancer cells. Mechanistically, we showed that YD23 induces changes in chromatin accessibility only in SMARCA4 deficient cells. Taking these observations together, we hypothesize that SMARCA2 degradation using YD23 is an attractive therapeutic strategy with promising therapeutic index in lung cancers with inactivating mutations in SMARCA4. The major objective of the proposed study is to provide preclinical evidence to guide future development of YD23 (or its analogs) in patients with SMARCA4 mutant lung cancer. While we have shown marked sensitivity of SMARCA4 mutant lung cancer cell lines to YD23, we still do not know the detailed mechanistic basis for this activity. Hence, we intend to perform gene expression, epigenetic and chromatin accessibility studies followed by integrative analysis to triangulate on direct target genes whose chromatin landscape is altered by presence or absence of SMARCA2 in SMARCA4 mutant cancer cells. While our in vitro cancer cell growth inhibitory studies are encouraging, a systematic exploration in vivo using various orthogonal model systems is required to aid the preclinical development of SMARCA2 degraders. Thus, we propose to determine the potential of YD23 mediated SMARCA2 degradation in SMARCA4 mutant xenograft and patient derived xenograft (PDX) model systems. Due to the unique microenvironment of lung cancer we will also test efficacy of YD23 in GEM models of lung cancer. Finally, SMARCA2 as a synthetic lethal partner of SMARCA4 has so far been described by in vitro experiments. In vivo genetic validation is critical to unequivocally demonstrate the requirement of a gene of interest in the development of a genetically defined subtype of cancer. Thus, we aim to perform CRISPR-Cas9 mediated Smarca2 genetic ablation to determine the extent of its involvement in the development and biology of Smarca4 mutant GEM models. In conclusion, our study is expected to provide mechanistic insight into the synthetic lethal genetic relationship between SMARCA2 and SMARCA4 and lay the foundation for future clinical development of SMARCA2 degraders as therapeutics.