Identification of Selective SWI/SNF Dependencies in Enzalutamide-Resistant Prostate Cancer

Enzalutamide (ENZA) is a potent second-generation antiandrogen commonly used to treat hormone-sensitive and castration-resistant prostate cancer (CRPC) patients. While initially effective, the response is only temporary and the disease almost always develops resistance. Given that many ENZA-resistant tumors are not driven by specific somatic mutations, there is increasing evidence that epigenetic factors can cause ENZA resistance. To explore how resistance arises we systematically tested all the epigenetic modifiers in castration-resistant and ENZA-resistant prostate cancer models using a custom epigenetic CRISPR library. From this, we identified and validated numerous epigenetic modifiers that were selectivity essential including SMARCC2, a core component of the SWI/SNF complex (or BAF complex) that regulates gene expression by altering DNA accessibility. Additionally, our data demonstrated canonical BAF complex dependency in ENZA-resistance that was also observed following the loss of DPF2, a canonical BAF-specific component. We showed that the chromatin occupancy of SMARCC2 and BRG1 was expanded in acquired ENZA resistance to the regions that overlap with transcriptional activity and CRPC-associated transcription factors that are significantly accessible in CRPC patients. Overall, our study revealed a regulatory role for SMARCC2 in ENZA-resistant prostate cancer and demonstrated the feasibility of targeting the SWI/SNF complex in late-stage PCa.