A Double-Negative Prostate Cancer Subtype is Vulnerable to SWI/SNF-Targeting Degrader Molecules
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 who die yearly of CRPC. 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 pro-proliferative transcription factor TCF7L2 and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer.
Authors
- Marika Lehner
- Irene Paassen
- DA Quigley
- Joanna Triscott (ORCID: https://orcid.org/0000-0002-0625-0524)
- Lia Mela (ORCID: https://orcid.org/0000-0002-0882-0586)
- Mark A. Rubin (ORCID: https://orcid.org/0000-0002-8321-9950)
- Simone de Brot (ORCID: https://orcid.org/0000-0003-3049-0103)
- Salvatore Piscuoglio (ORCID: https://orcid.org/0000-0003-2686-2939)
- Phillip Thienger
- Robert L. Yauch (ORCID: https://orcid.org/0000-0001-9478-6283)
- Bence Dániel (ORCID: https://orcid.org/0000-0002-2410-8767)
- Andrej Benjak (ORCID: https://orcid.org/0000-0003-4522-6575)
- Y. Chen
- Alina Naveed (ORCID: https://orcid.org/0000-0002-1820-9908)
- Xiaosai Yao (ORCID: https://orcid.org/0000-0001-9729-0726)
- Nicholas Lillis
- Philip Rubin
- Sona Shah
- Minyi Shi (ORCID: https://orcid.org/0000-0003-1616-8353)
- Giada Andrea Cassanmagnago
- Julien Tremblay
- Haiyuan Yu
- Marco Bolis
Institutions
- University of Bern (CH)
- Bern University of Applied Sciences (CH)
- Memorial Sloan Kettering Cancer Center (US)
- Humanitas University (IT)
- University of California, San Francisco (US)
- Mario Negri Institute for Pharmacological Research (IT)
- Cornell University (US)
- Acentech (United States) (US)
- Institute of Oncology Research (CH)
- Dana-Farber Cancer Institute (US)
- Princess Máxima Center (NL)
- Kaiser Permanente South San Francisco Medical Center (US)
- Fondazione Humanitas per la Ricerca (IT)
- Dipartimento dell Educazione della Cultura e dello Sport (CH)
- University of San Francisco (US)
- Stanford University (US)
Publication Details
- Journal
- Cancer Research
- Published
- 2026-01-14
- DOI
- https://doi.org/10.1158/0008-5472.can-25-2928
- Primary Topic
- Chromatin Remodeling and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- Prostate Cancer Foundation
- Eli Lilly and Company
- Memorial Sloan-Kettering Cancer Center
- Universität Basel
- University of Bern
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Astellas Pharma
- Genentech
- National Cancer Institute
- DOD Prostate Cancer Research Program