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

项目摘要 肺癌是一种毁灭性的疾病，仍然是癌症死亡的首要原因。尽管最近 然而，随着癌症的发展，大多数肺癌患者缺乏有效的治疗选择，这突出了迫切需要 其他治疗方法。基因组学研究已经确定了基因组中亚基的频繁突变， SWI/SNF染色质重塑复合物（包括SMARCA4和ARID1A）在非小细胞肺癌中的表达 在晚期疾病中的频率高达33%，使其成为肺中最常见的突变复合体 癌我们最近证明Smarca 4在小鼠中作为一种真正的肿瘤抑制因子， p53缺失和Kras激活。重要的是，SMARCA4突变癌细胞对 新型小分子IACS-10759对氧化磷酸化（OXPHOS）的抑制作用。机械地，我们 表明SMARCA 4缺陷细胞对能量应激的转录反应迟钝， 治疗相关的脆弱性 将这些观察结果结合在一起，我们假设使用IACS-10759的OXPHOS抑制是一种有效的方法。 具有SWI/SNF复合物突变的肺癌的有吸引力的治疗策略。的主要目标 本研究旨在揭示SWI/SNF突变体中代谢重新连接的机制基础， 提供临床前证据，以指导IACS-10759在SWI/SNF突变肺患者中的未来临床研究 癌由于肺癌独特的微环境包括局部高氧分压， 研究以代谢为靶点的治疗药物。因此，我们将测试IACS-10759在 肺癌的GEM模型。此外，PDX模型已成为帮助指导治疗的强大工具 战略布局因此，我们建议确定在各种SWI/SNF突变体PDX中OXPHOS抑制的潜力。 模型系统虽然我们的初步数据表明IACS-10759治疗导致肿瘤生长抑制， 预期协同组合策略在功效上甚至更优越。因此，我们建议确定 通过使用化学遗传学筛选与IACS-10759协同的最佳组合药剂。在这里，我们将使用 CRISPR-Cas9和针对FDA批准药物靶向基因的定制设计的指导RNA文库 （FDAome）。我们将通过在体内进行一对一药物组合研究来验证筛选结果。 最后，我们的初步数据表明，SMARCA 2是表达PGC1 α所必需的，PGC1 α是一种主要的 在SMARCA4突变细胞中，线粒体生物发生和OXPHOS的转录调节因子。我们知道从 我们发表的工作表明，PGC1 α在SMARCA 4缺陷细胞中是必需的。因此，我们假设SMARCA 2 是一种生存因子，也是SMARCA 4缺陷细胞中代谢重新连接的主要驱动因素， 方式总之，我们的研究有望为代谢失调提供机制性的见解。 SWI/SNF突变型肺癌，为OXPHOS抑制剂的未来临床开发奠定基础 as therapeutics治疗.

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.