biostudies-literatureUnknownThienger PNCI NIH HHSProteolysis 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). The CRPC-WNT subgroup represents 11% of around 400,000 cases of CRPC worldwide who die yearly of CRPC. We discovered that SWI/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 (TCF4) in CRPC-WNT. Functionally, TCF7L2 maintains proliferation via bioRxiv : the preprint server for biology2024.03.24.586276https://www.ebi.ac.uk/biostudies/studies/S-EPMC12424701biostudies-literatureA double-negative prostate cancer subtype is vulnerable to SWI/SNF-targeting degrader molecules.PMC12424701P50 CA275741Shah SRTriscott JLillis NShi MQuigley DAYu HPaassen ICassanmagnago GADaniel BChen YLehner MRubin PDBolis MThienger PLeung AKYauch RLPiscuoglio SYao XNaveed ABenjak Ade Brot STremblay JBeltran HRubin MAMela LNg CKYfalseA double-negative prostate cancer subtype is vulnerable to SWI/SNF-targeting degrader molecules.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). The CRPC-WNT subgroup represents 11% of around 400,000 cases of CRPC worldwide who die yearly of CRPC. We discovered that SWI/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 (TCF4) in CRPC-WNT. Functionally, TCF7L2 maintains proliferation via 2025-01-01T00:00:00Z2025 Sep2026-04-16T03:21:44.45Z2026-04-16T03:12:45.909ZS-EPMC124247014094997210.1101/2024.03.24.586276