SMARCA4/2 loss reduces BCL-xL expression and confers a druggable MCL1 dependency in cancer

SMARCA4 (BRG1) and SMARCA2 (BRM) are the mutually exclusive ATPase subunits of the SWI/SNF chromatin remodeling complexes, often altered in cancers. Concurrent loss of SMARCA4/2 is found in some aggressive cancer types, including small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), a rare and lethal ovarian cancer affecting young women, and a subset of non-small cell lung cancers (NSCLCs), associated with chemotherapy resistance and poor outcome. Through a functional genetic approach, we identified that inhibition of MCL1, an anti-apoptotic protein of the BCL-2 family, is synthetic lethal with SMARCA4/2 loss in these cancer cells. MCL1 suppression by RNAi or a small molecule inhibitor, S63845, selectively induced apoptosis in SMARCA4/2-deficient SCCOHT and NSCLC cells but not in SMARCA4/2-proficient controls. Mechanistically, SMARCA4/2 directly promotes mRNA expression of BCL-xL, encoding another key anti-apoptotic protein of the BCL-2 family; SMARCA4/2 loss therefore results in downregulation of BCL-xL, leading to MCL1 dependency to suppress apoptosis in these cancer cells. Furthermore, single-agent treatment of S63845 resulted in significant suppression of tumor growth in patient-derived xenografts of SMARCA4/2-deficient NSCLC and SCCOHT. Collectively, our work uncovered MCL1 as a synthetic lethal target in SMARCA4/2-deficient cancers that may be exploited therapeutically.