Androgen receptor-negative prostate cancer is vulnerable to SWI/SNF-targeting degrader molecules

The switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex is frequently deregulated during progression to castration-resistant prostate cancer (CRPC). Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases offer a novel approach to interfere with androgen receptor (AR) signaling in AR-dependent CRPC (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF ATPase targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT-signaling dependent AR-negative CRPC (CRPC-WNT), which accounts for about 10% of all clinical CRPC cases. In CRPC-WNT models, we discovered that SWI/SNF ATPase SMARCA4 depletion interfered with WNT signaling via the master transcriptional regulator TCF7L2 (TCF4). Functionally, TCF7L2 maintains proliferation via the MAPK signaling axis in this subtype of CRPC by forming a complex with β-Catenin and AP-1 transcription factor c-JUN. These data suggest a mechanistic rationale for MAPK inhibition or interventions that disrupt the formation of the pro-proliferative TCF7L2-β-Catenin-JUN complex in the CRPC-WNT subclass of advanced prostate cancer.