A double-negative prostate cancer subtype is vulnerable to SWI/SNF-targeting degrader molecules PMID: 40949972

GLP-1 and Obesity Research

2026-08-18

A double-negative prostate cancer subtype is vulnerable to SWI/SNF-targeting degrader molecules

bioRxiv. 2025 Sep 3:2024.03.24.586276. doi: 10.1101/2024.03.24.586276.

Phillip Thienger ¹ , Irene Paassen ¹ , Xiaosai Yao ² ³ , Philip D Rubin ¹ , Marika Lehner ¹ , Nicholas Lillis ⁴ , Andrej Benjak ¹ , Sagar R Shah ⁵ , Alden King-Yung Leung ⁵ , Simone de Brot ⁶ , Alina Naveed ¹ , Bence Daniel ⁷ , Minyi Shi ⁷ , Julien Tremblay ³ , Joanna Triscott ¹ , Giada Andrea Cassanmagnago ⁸ ⁹ ¹⁰ , Marco Bolis ⁸ ⁹ ¹⁰ , Lia Mela ¹ , Himisha Beltran ¹¹ , Yu Chen ¹² ¹³ ¹⁴ , Salvatore Piscuoglio ¹⁵ ¹⁶ , Haiyuan Yu ⁵ , Charlotte K Y Ng ¹⁷ ¹⁸ , David A Quigley ⁴ ¹⁹ ²⁰ , Robert L Yauch ² , Mark A Rubin ¹ ¹⁸ ²¹

Affiliations

1. Department for Biomedical Research, University of Bern, Bern, 3008, Switzerland.
2. Department of Molecular Oncology, Genentech, South San Francisco, CA, USA.
3. Department of Computational Sciences, Genentech, South San Francisco, CA, USA.
4. Department of Urology, University of California, San Francisco, CA, USA.
5. Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA.
6. COMPATH, Institute of Animal Pathology, University of Bern, Bern, Switzerland.
7. Department of Proteomics and Genomic Technologies, Genentech, South San Francisco, CA 94080.
8. Computational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche 'Mario Negri' IRCCS, Via Mario Negri 2, 20156 Milano, Italy.
9. Institute of Oncology Research, Bioinformatics Core Unit, Bellinzona, TI 6500, Switzerland.
10. Università Della Svizzera Italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland.
11. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
12. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
13. Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, 10065, USA.
14. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
15. IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy.
16. Department of Biomedicine, University Hospital Basel, University of Basel, 4001 Basel, Switzerland.
17. SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
18. Bern Center for Precision Medicine, 3008, Bern, Switzerland.
19. Department of Epidemiology & Biostatistics, University of California, San Francisco, CA, USA.
20. Helen Diller Family Comprehensive Cancer Center, UCSF.
21. Inselspital, 3010, Bern, Switzerland.

Abstract

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.