BET inhibitors reduce tumor growth in preclinical models of gastrointestinal gene signature–positive castration-resistant prostate cancer
A subgroup (~20%-30%) of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by 2 GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlated with adverse clinical outcomes to androgen receptor (AR) signaling inhibitor treatment and shorter overall survival. Bromo- and extraterminal domain inhibitors (BETi) downregulated HNF1A, HNF4G, and the GI transcriptome in multiple CRPC models, including cell lines, patient-derived organoids, and patient-derived xenografts, whereas AR and the androgen-dependent transcriptome were largely spared. Accordingly, BETi selectively inhibited growth of GI transcriptome-positive preclinical models of prostate cancer. Mechanistically, BETi inhibited BRD4 binding at enhancers globally, including both AR and HNF4G bound enhancers, while gene expression was selectively perturbed. Restoration of HNF4G expression in the presence of BETi rescued target gene expression without rescuing BRD4 binding. This suggests that inhibition of master transcription factors expression underlies the selective transcriptional effects of BETi.
Authors
- Holly M. Nguyen (ORCID: https://orcid.org/0000-0002-6331-8089)
- Shipra Shukla (ORCID: https://orcid.org/0000-0001-9537-9540)
- Sarah Attwell
- Anuradha Gopalan (ORCID: https://orcid.org/0009-0007-6017-0991)
- Ping Chi
- Patrick Trojer (ORCID: https://orcid.org/0000-0001-9969-9154)
- Eva Corey (ORCID: https://orcid.org/0000-0002-9244-3807)
- Ekta Khurana (ORCID: https://orcid.org/0000-0002-4351-7566)
- Mohini R. Pachai (ORCID: https://orcid.org/0000-0003-1143-0607)
- Irina Ostrovnaya (ORCID: https://orcid.org/0000-0003-1783-0070)
- Juan Yan (ORCID: https://orcid.org/0000-0001-7130-945X)
- Eric Campeau (ORCID: https://orcid.org/0000-0002-7121-9785)
- Jennifer L. Conner (ORCID: https://orcid.org/0009-0000-9738-5100)
- Gabriella Bayshtok (ORCID: https://orcid.org/0000-0001-5968-9584)
- Woo Hyun Cho (ORCID: https://orcid.org/0000-0002-8299-8008)
- Dan Li (ORCID: https://orcid.org/0000-0002-8777-4580)
- Yu Chen (ORCID: https://orcid.org/0000-0002-0171-3884)
- Nicholas A. Teri
- Dana M. Schoeps
- Marjorie Roskes (ORCID: https://orcid.org/0000-0002-2364-5405)
- Anisha B. Tehim
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- University of Washington (US)
- Cornell University (US)
- Emory University Hospital (US)
- Intarcia Therapeutics (United States) (US)
- Cancer Research And Biostatistics (US)
- Epigénétique et Destin Cellulaire (FR)
- Weill Cornell Medicine (US)
- Seattle University (US)
- Epigenomics (Germany) (DE)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-06-24
- DOI
- https://doi.org/10.1172/jci180378
- Citations
- 2
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 1.61