Abstract
Proteolysis-targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases 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 that die yearly. SWI/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 in CRPC-WNT. Functionally, TCF7L2 maintained proliferation via the MAPK signaling axis in this subtype of CRPC. Together, these data provide a mechanistic rationale for interventions that perturb DNA binding of the proproliferative transcription factor TCF7L2 and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer. SIGNIFICANCE: SWI/SNF-targeting agents interfere with a lineage-defining molecular axis in the WNT signaling-dependent, androgen receptor-negative subtype of prostate cancer, which accounts for around 10% of castration-resistant tumors.