Phillip Thienger, Irene Paassen, Xiaosai Yao, Philip Rubin, Marika Lehner, Nicholas Lillis, Andrej Benjak, Sagar R. Shah, Alden King-Yung Leung, Simone de Brot, Alina Naveed, Bence Dániel, Minyi Shi, Julien Tremblay, Joanna Triscott, Giada Andrea Cassanmagnago, Marco Bolis, Lia Mela, Himisha Beltran, Y. Chen, Salvatore Piscuoglio, Haiyuan Yu, Charlotte K.Y. Ng, DA Quigley, Robert L. Yauch, Mark A. Rubin
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.