Identification of selective SWI/SNF dependencies in enzalutamide-resistant prostate cancer

Enzalutamide is a potent second-generation antiandrogen commonly used to treat hormone-sensitive and castration-resistant prostate cancer (CRPC) patients. While initially effective, the disease almost always develops resistance. Given that many enzalutamide-resistant tumors lack specific somatic mutations, there is strong evidence that epigenetic factors can cause enzalutamide resistance. To explore how resistance arises, we systematically test all epigenetic modifiers in several models of castration-resistant and enzalutamide-resistant prostate cancer with a custom epigenetic CRISPR library. From this, we identify and validate SMARCC2, a core component of the SWI/SNF complex, that is selectivity essential in enzalutamide-resistant models. We show that the chromatin occupancy of SMARCC2 and BRG1 is expanded in enzalutamide resistance at regions that overlap with CRPC-associated transcription factors that are accessible in CRPC clinical samples. Overall, our study reveals a regulatory role for SMARCC2 in enzalutamide-resistant prostate cancer and supports the feasibility of targeting the SWI/SNF complex in late-stage PCa.