Project 2

点击翻译按钮获取中文摘要

Summary/Abstract SMARCA4-mutant NSCLC represents a prevalent, aggressive subset in urgent need of effective therapies. SMARCA4 encodes BRG1, a key ATPase subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. SMARCA4 mutations are present in 9-11% of patients with NSCLC, with truncating, BRG1-inactivating mutations comprising greater than one-third of these alterations. Thus, SMARCA4 is one of the most frequently mutated genes in NSCLC that has no targeted treatment option. SMARCA4 mutations often overlap with molecular alterations (KEAP1 and STK11 mutations) that decrease sensitivity to traditional therapeutic approaches such as immunotherapy and chemotherapy. In a recent study from the Kim laboratory, BRG1 deficiency increased DNA replicative stress and enhanced sensitivity to ATR pathway inhibition in preclinical lung cancer models. Ataxia telangectasia mutated and Rad3-related (ATR) kinase is a key regulator of cellular response to replication stress that activates the DNA damage checkpoint in response to single strand DNA created during the resection of DNA double-strand breaks or due to defects in DNA replication. Here, we will test the hypothesis that the underlying replication stress associated with BRG1 deficiency provides a therapeutic opportunity for SMARCA4 mutant lung cancer; we will identify drug combinations effective with ATR inhibition. We will build upon our discoveries by (Aim 1) comprehensively characterizing hallmarks of replication stress and assessing immune system activation in NSCLC clinical specimens with SMARCA4 mutations, (Aim 2) evaluating sensitivity of SMARCA4-mutant NSCLCs to therapies targeting replication stress defects, and (Aim 3) performing pre-clinical studies to assess the anti-tumor effects of ATR inhibition in combination with anti-PD1/PD-L1 immunotherapy. We will leverage existing preclinical models of SMARCA4- mutant, BRG1-deficient NSCLC generated in the Kim Lab (CRISPR-generated isogenic BRG1-deficient lines, GEMM) and Hata Lab (BRG1-deficient patient-derived xenograft (PDX)), together with patient samples from Drs. Dagogo-Jack and Cheng to evaluate the antitumor activity of rational combinations of candidate drugs to support future development of clinical trials. Overall, the studies proposed in this grant aim to advance the care of patients with SMARCA4-mutant NSCLC by exploring a novel, promising approach that exploits a unique vulnerability induced by BRG1 deficiency. We envision that the work proposed in this study will inform clinical trials exploring novel combination therapy approaches (ATR inhibition plus immunotherapy or gemcitabine) in patients with BRG1-deficient NSCLC, potentially paving the way for future approvals.