A Double-Negative Prostate Cancer Subtype Is Vulnerable to SWI/SNF-Targeting Degrader Molecules

Phillip Thienger; Irene Paassen; Xiaosai Yao; Philip D Rubin; Marika Lehner; Nicholas Lillis; Andrej Benjak; Sagar R Shah; Alden King-Yung Leung; Simone de Brot; Alina Naveed; Bence Daniel; Minyi Shi; Julien Tremblay; Joanna Triscott; Giada Andrea Cassanmagnago; Marco Bolis; Lia Mela; Himisha Beltran; Yu Chen; Salvatore Piscuoglio; Haiyuan Yu; Charlotte K Y Ng; David A Quigley; Robert L Yauch; Mark A Rubin

doi:10.1158/0008-5472.CAN-25-2928

A Double-Negative Prostate Cancer Subtype Is Vulnerable to SWI/SNF-Targeting Degrader Molecules

Cancer Res. 2026 Apr 2;86(7):1570-1585. doi: 10.1158/0008-5472.CAN-25-2928.

Authors

Phillip Thienger¹, Irene Paassen¹, Xiaosai Yao^{2

3}, Philip D Rubin¹, Marika Lehner¹, Nicholas Lillis⁴, Andrej Benjak¹, Sagar R Shah⁵, Alden King-Yung Leung⁵, Simone de Brot⁶, Alina Naveed¹, Bence Daniel⁷, Minyi Shi⁷, Julien Tremblay³, Joanna Triscott¹, Giada Andrea Cassanmagnago^{8

9

10}, Marco Bolis^{8

9

10}, Lia Mela¹, Himisha Beltran¹¹, Yu Chen^{12

13

14}, Salvatore Piscuoglio¹⁵, Haiyuan Yu⁵, Charlotte K Y Ng^{16

17}, David A Quigley^{4

18

19}, Robert L Yauch², Mark A Rubin^{1

17

20}

Affiliations

¹ Department for Biomedical Research, University of Bern, Bern, Switzerland.
² Department of Molecular Oncology, Genentech, South San Francisco, California.
³ Department of Computational Sciences, Genentech, South San Francisco, California.
⁴ Department of Urology, University of California, San Francisco, California.
⁵ Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York.
⁶ COMPATH, Institute of Animal Pathology, University of Bern, Bern, Switzerland.
⁷ Department of Proteomics and Genomic Technologies, Genentech, South San Francisco, California.
⁸ Computational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche 'Mario Negri' IRCCS, Milano, Italy.
⁹ Bioinformatics Core Unit, Institute of Oncology Research, Bellinzona, Switzerland.
¹⁰ Faculty of Biomedical Sciences, Università Della Svizzera Italiana (USI), 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, New York.
¹³ Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, New York.
¹⁴ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
¹⁵ IRCCS Humanitas Research Hospital Milan, Italy.
¹⁶ SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
¹⁷ Bern Center for Precision Medicine, Bern, Switzerland.
¹⁸ Department of Epidemiology and Biostatistics, University of California, San Francisco, California.
¹⁹ Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California.
²⁰ Inselspital, University Hospital of Bern, Bern, Switzerland.

Abstract

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 that die yearly. 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 proproliferative transcription factor TCF7L2 and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer.

Significance: SWI/SNF-targeting agents interfere with a lineage-defining molecular axis in the WNT signaling-dependent, androgen receptor-negative subtype of prostate cancer, which accounts for around 10% of castration-resistant tumors.

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation / drug effects
DNA Helicases* / antagonists & inhibitors
DNA Helicases* / genetics
DNA Helicases* / metabolism
Gene Expression Regulation, Neoplastic / drug effects
Humans
Male
Mice
Nuclear Proteins* / antagonists & inhibitors
Nuclear Proteins* / genetics
Nuclear Proteins* / metabolism
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Prostatic Neoplasms, Castration-Resistant* / genetics
Prostatic Neoplasms, Castration-Resistant* / metabolism
Prostatic Neoplasms, Castration-Resistant* / pathology
Receptors, Androgen / genetics
Receptors, Androgen / metabolism
Transcription Factor 7-Like 2 Protein* / genetics
Transcription Factor 7-Like 2 Protein* / metabolism
Transcription Factors* / antagonists & inhibitors
Transcription Factors* / genetics
Transcription Factors* / metabolism
Wnt Signaling Pathway / drug effects
Xenograft Model Antitumor Assays

Substances

Receptors, Androgen
Transcription Factors
SMARCA4 protein, human
Transcription Factor 7-Like 2 Protein
Nuclear Proteins
DNA Helicases
TCF7L2 protein, human
AR protein, human

Abstract

MeSH terms

Substances

Grants and funding