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

The switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex becomes frequently deregulated in advanced 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 castration-resistant prostate cancer (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF-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). We discovered that SWI/SNF ATPase SMARCA4 depletion interfered with the WNT master transcriptional regulator TCF7L2 (TCF4) in CRPC-WNT. Overall design: Patient-derived organoids (WCM1078) were treated with A947 (SMARCA2/SMARCA4 targeting PROTAC) and A858 (SMARCA-binder control). RNA-seq: Organoids were treated with A858 or A947 (1µM) for 24h and 48h (3 biological replicates per condition). ChIP-seq: Organoids were treated with A858 or A947 (1µM) for 4h (2 biological replicates per condition). ATAC-seq: Organoids were treated with A858 or A947 (1µM) for 4h (3 biological replicates per condition). scRNA: Organoids were treated for 72h with a control epimer (A858) or active compound (A947) at 1 µM. PRO-cap: Organoids were treated for 24h with a control epimer (A858) or active compound (A947) at 1 µM.