bioRxiv : the preprint server for biology · 2025
A double-negative prostate cancer subtype is vulnerable to SWI/SNF-targeting degrader molecules.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
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Thienger Phillip, Paassen Irene, Yao Xiaosai, Rubin Philip D, Lehner Marika, Lillis Nicholas, Benjak Andrej, Shah Sagar R, Leung Alden King-Yung, de Brot Simone, Naveed Alina, Daniel Bence, Shi Minyi, Tremblay Julien, Triscott Joanna, Cassanmagnago Giada Andrea, Bolis Marco, Mela Lia, Beltran Himisha, Chen Yu, Piscuoglio Salvatore, Yu Haiyuan, Ng Charlotte K Y, Quigley David A, Yauch Robert L, Rubin Mark A
Аннотация
Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases offer a novel approach to 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 who die yearly of CRPC. We discovered that SWI/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 (TCF4) in CRPC-WNT. Functionally, TCF7L2 maintains proliferation via the MAPK signaling axis in this subtype of CRPC. These data suggest a mechanistic rationale for interventions that perturb the DNA binding of the pro-proliferative TCF7L2 transcription factor (TF) and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer.