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). SWI/SNF ATPase degrader molecules, also known as Proteolysis targeting chimera (PROTAC), offer a novel approach to tackle resistance to androgen receptor (AR) antagonists in AR-dependent CRPC (CRPC-AR). However, the frequent emergence of AR-negative CRPC remains a major clinical hurdle. We investigated SWI/SNF ATPase targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment reduced the viability of both CRPC-AR and WNT-signaling dependent CRPC (CRPC-WNT), which accounts for about 10% of all clinical CRPC cases. In CRPC-WNT, we characterized that SWI/SNF ATPase SMARCA4 depletion interfered with WNT signaling via the master transcriptional regulator TCF7L2 (TCF4). Functionally, TCF7L2 maintains proliferation via the AP-1/MAPK signaling axis in this subtype of CRPC. We performed a ChIP-seq experiment using 2 biological replicates of WCM1078 treated with A858 or A947 (1µM) for 24h. A947, is a novel PROTAC degrader that co-binds the bromodomain in SMARCA2/SMARCA4/PBRM1 and the von Hippel-Lindau (VHL) ubiquitin ligase12. A858 is A947's inactive epimer control (SMARCA-binder control). Both molecules were synthesized at Genentech. >>>Submitter states that raw data are not available due to patient privacy concerns.<<<