PRC2-mediated repression of SMARCA2 predicts EZH2 inhibitor activity in SWI/SNF mutant tumors

Significance Targeting epigenetic dependencies caused by mutations in chromatin-modifying enzymes represents a novel therapeutic approach in cancer. Notably, cancers harboring mutations in the SNF5 subunit of the SWI/SNF chromatin remodeling complex have been shown to be susceptible to small-molecule inhibitors of the EZH2 histone methyltransferase that are currently in clinical development. We demonstrate that EZH2 inhibition can be effective in SMARCA4 mutant cancers that concurrently transcriptionally silence the paralog helicase SMARCA2. SMARCA2 is directly suppressed by EZH2, and SMARCA2 expression levels predict EZH2 inhibitor activity in other SWI/SNF mutant contexts, including ARID1A mutant tumors. These data provide insight into the utility of EZH2 inhibitors in SWI/SNF mutant tumors and have important implications regarding predictive diagnostics. Subunits of the SWI/SNF chromatin remodeling complex are frequently mutated in human cancers leading to epigenetic dependencies that are therapeutically targetable. The dependency on the polycomb repressive complex (PRC2) and EZH2 represents one such vulnerability in tumors with mutations in the SWI/SNF complex subunit, SNF5; however, whether this vulnerability extends to other SWI/SNF subunit mutations is not well understood. Here we show that a subset of cancers harboring mutations in the SWI/SNF ATPase, SMARCA4, is sensitive to EZH2 inhibition. EZH2 inhibition results in a heterogenous phenotypic response characterized by senescence and/or apoptosis in different models, and also leads to tumor growth inhibition in vivo. Lower expression of the SMARCA2 paralog was associated with cellular sensitivity to EZH2 inhibition in SMARCA4 mutant cancer models, independent of tissue derivation. SMARCA2 is suppressed by PRC2 in sensitive models, and induced SMARCA2 expression can compensate for SMARCA4 and antagonize PRC2 targets. The induction of SMARCA2 in response to EZH2 inhibition is required for apoptosis, but not for growth arrest, through a mechanism involving the derepression of the lysomal protease cathepsin B. Expression of SMARCA2 also delineates EZH2 inhibitor sensitivity for other SWI/SNF complex subunit mutant tumors, including SNF5 and ARID1A mutant cancers. Our data support monitoring SMARCA2 expression as a predictive biomarker for EZH2-targeted therapies in the context of SWI/SNF mutant cancers.