A double-negative prostate cancer subtype is vulnerable to SWI/SNF-targeting degrader molecules

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Proteolysis targeting chimera (PROTAC) therapies offer a novel strategy to target androgen receptor (AR) signaling in AR-dependent castration-resistant prostate cancer (CRPC-AR).
• The efficacy of SWI/SNF ATPase-targeting agents in AR-negative CRPC, particularly the WNT-signaling dependent subtype (CRPC-WNT), remains largely unexplored.
• CRPC-WNT accounts for a significant proportion of CRPC deaths globally.

Purpose of the Study:

• To investigate the therapeutic potential of SWI/SNF-targeting agents in AR-negative CRPC, specifically the CRPC-WNT subgroup.
• To elucidate the molecular mechanisms by which SWI/SNF targeting impacts CRPC-WNT cell viability.
• To identify potential therapeutic targets within the CRPC-WNT signaling pathway.

Main Methods:

• Utilized cell lines and organoid models derived from CRPC.
• Administered SWI/SNF-targeting PROTACs to evaluate their impact on cell viability.
• Investigated the interaction between SWI/SNF ATPase SMARCA4, TCF7L2, and the MAPK signaling pathway in CRPC-WNT.

Main Results:

• SWI/SNF-targeting PROTAC treatment reduced the viability of both CRPC-AR and CRPC-WNT models.
• SMARCA4 depletion in CRPC-WNT models was found to interfere with the transcriptional regulator TCF7L2.
• TCF7L2 was identified as a key driver of proliferation in CRPC-WNT, functioning through the MAPK signaling axis.

Conclusions:

• SWI/SNF-targeting therapies demonstrate efficacy against both AR-dependent and AR-negative WNT-signaling CRPC.
• SMARCA4 depletion disrupts TCF7L2-mediated proliferation in CRPC-WNT by affecting the MAPK pathway.
• Targeting TCF7L2 DNA binding or MAPK signaling presents a promising therapeutic strategy for CRPC-WNT.