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
Department for Biomedical Research, University of Bern, Bern, 3008, Switzerland.
Department of Molecular Oncology, Genentech, South San Francisco, CA, USA.
bioRxiv. 2025 Sep 3:2024.03.24.586276. doi: 10.1101/2024.03.24.586276.
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.
靶向蛋白水解嵌合体（PROTAC）疗法通过降解SWI/SNF ATP酶，为干扰雄激素受体（AR）依赖性去势抵抗性前列腺癌（CRPC-AR）中的AR信号传导提供了一种新方法。为了探索SWI/SNF疗法在AR敏感型CRPC之外的效用，我们研究了AR阴性CRPC中靶向SWI/SNF的药物。对细胞系和类器官模型进行SWI/SNF靶向PROTAC治疗，不仅降低了CRPC-AR的活力，还降低了WNT信号依赖性AR阴性CRPC（CRPC-WNT）的活力。CRPC-WNT亚组在全球每年死于CRPC的约40万例CRPC病例中占11%。我们发现，在CRPC-WNT中，SWI/SNF ATP酶SMARCA4的缺失会干扰主要转录调节因子TCF7L2（TCF4）。在功能上，TCF7L2通过MAPK信号轴在这种CRPC亚型中维持增殖。这些数据为在晚期前列腺癌的CRPC-WNT亚类中干扰促增殖TCF7L2转录因子（TF）的DNA结合和/或直接抑制MAPK信号传导的干预措施提供了机制依据。
