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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261446 | GEO | 2024/03/18

REPOSITORIES: GEO

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