Identification of selective SWI/SNF dependencies in enzalutamide-resistant prostate cancer
Enzalutamide is a potent second-generation antiandrogen commonly used to treat hormone-sensitive and castration-resistant prostate cancer (CRPC) patients. While initially effective, the disease almost always develops resistance. Given that many enzalutamide-resistant tumors lack specific somatic mutations, there is strong evidence that epigenetic factors can cause enzalutamide resistance. To explore how resistance arises, we systematically test all epigenetic modifiers in several models of castration-resistant and enzalutamide-resistant prostate cancer with a custom epigenetic CRISPR library. From this, we identify and validate SMARCC2, a core component of the SWI/SNF complex, that is selectivity essential in enzalutamide-resistant models. We show that the chromatin occupancy of SMARCC2 and BRG1 is expanded in enzalutamide resistance at regions that overlap with CRPC-associated transcription factors that are accessible in CRPC clinical samples. Overall, our study reveals a regulatory role for SMARCC2 in enzalutamide-resistant prostate cancer and supports the feasibility of targeting the SWI/SNF complex in late-stage PCa.
Authors
- Paloma Cejas (ORCID: https://orcid.org/0000-0002-2090-7748)
- Chia-Chi Flora Huang (ORCID: https://orcid.org/0000-0002-2150-3139)
- Nathan A. Lack (ORCID: https://orcid.org/0000-0001-7399-5844)
- Ivan Pak Lok Yu
- Sonia H.Y. Kung (ORCID: https://orcid.org/0000-0002-9230-8939)
- James T. Lynch (ORCID: https://orcid.org/0009-0002-8260-5355)
- Bengul Gokbayrak (ORCID: https://orcid.org/0000-0003-0504-6078)
- Umut Berkay Altıntaş (ORCID: https://orcid.org/0000-0002-0861-5013)
- Tamer T. Önder (ORCID: https://orcid.org/0000-0002-2372-9158)
- Ladan Fazli (ORCID: https://orcid.org/0000-0001-6488-4245)
- Ceyda Açılan (ORCID: https://orcid.org/0000-0002-8936-3267)
- Tunç Morova (ORCID: https://orcid.org/0000-0002-4062-6185)
- Henry W. Long (ORCID: https://orcid.org/0000-0001-6849-6629)
- Shreyas Lingadahalli (ORCID: https://orcid.org/0000-0002-9609-6486)
- Batuhan Mert Kalkan (ORCID: https://orcid.org/0000-0002-3288-0968)
- Tugba Bagcı-Önder (ORCID: https://orcid.org/0000-0003-3646-2613)
- Akane Kawamura (ORCID: https://orcid.org/0000-0003-1169-5082)
- Betul Ersoy Fazlioglu
Institutions
- AstraZeneca (United Kingdom) (GB)
- Brigham and Women's Hospital (US)
- Koç University (TR)
- Harvard University (US)
- University of British Columbia (CA)
- University of Oxford (GB)
- Hospital La Paz Institute for Health Research (ES)
- Dana-Farber Cancer Institute (US)
- The Prostate Centre (GB)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Dana-Farber Brigham Cancer Center (US)
- Newcastle University (GB)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-02-04
- DOI
- https://doi.org/10.1038/s42003-024-07413-w
- Citations
- 4
- Primary Topic
- Chromatin Remodeling and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- AstraZeneca
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Türkiye Bilimsel ve Teknolojik Araştırma Kurumu
- Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi