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 targeting SWI/SNF ATPases interfere with androgen receptor (AR) signaling in AR-dependent castration-resistant prostate cancer (CRPC-AR).
• The efficacy of SWI/SNF-targeting agents in AR-negative CRPC remains largely unexplored.
• AR-negative CRPC, particularly the WNT signaling-dependent subtype (CRPC-WNT), represents a significant unmet clinical need.

Purpose of the Study:

• To investigate the therapeutic potential of SWI/SNF-targeting agents in AR-negative CRPC.
• To elucidate the mechanisms by which SWI/SNF depletion affects CRPC-WNT cells.
• To identify novel therapeutic strategies for advanced prostate cancer.

Main Methods:

• Treatment of CRPC cell lines and organoid models with SWI/SNF-targeting PROTACs.
• Assessment of cell viability and signaling pathway alterations.
• Depletion of SWI/SNF ATPase SMARCA4 and analysis of its downstream targets, including TCF7L2 and MAPK signaling.

Main Results:

• SWI/SNF-targeting PROTAC treatment reduced the viability of both CRPC-AR and CRPC-WNT cells.
• SMARCA4 depletion in CRPC-WNT cells interfered with the transcriptional regulator TCF7L2.
• TCF7L2 was found to maintain proliferation in CRPC-WNT via the MAPK signaling axis.

Conclusions:

• SWI/SNF-targeting therapies are effective against both AR-dependent and WNT-dependent CRPC.
• Perturbing TCF7L2 DNA binding or inhibiting MAPK signaling presents a viable therapeutic strategy for CRPC-WNT.
• These findings offer a mechanistic basis for novel treatment approaches in advanced prostate cancer.