2. Academic Validation
  3. A double-negative prostate cancer subtype is vulnerable to SWI/SNF-targeting degrader molecules

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

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.
PMID: 40949972 DOI: 10.1101/2024.03.24.586276
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.

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