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ResearchIn-Press PreviewCell biologyGeneticsOncology Open Access | 10.1172/JCI180378

BET inhibitors reduce tumor growth in preclinical models of gastrointestinal gene signature-positive castration-resistant prostate cancer

Shipra Shukla,1 Dan Li,1 Woo Hyun Cho,1 Dana M. Schoeps,1 Holly M. Nguyen,2 Jennifer L. Conner,2 Marjorie L. Roskes,3 Anisha Tehim,3 Gabriella Bayshtok,1 Mohini R. Pachai,1 Juan Yan,1 Nicholas A. Teri,1 Eric Campeau,4 Sarah Attwell,4 Patrick Trojer,5 Irina Ostrovnaya,6 Anuradha Gopalan,7 Ekta Khurana,3 Eva Corey,2 Ping Chi,1 and Yu Chen1

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Shukla, S. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Li, D. in: PubMed | Google Scholar |

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Cho, W. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Yan, J. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Trojer, P. in: PubMed | Google Scholar |

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Ostrovnaya, I. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Gopalan, A. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Khurana, E. in: PubMed | Google Scholar |

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Corey, E. in: PubMed | Google Scholar |

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Chi, P. in: PubMed | Google Scholar |

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Urology, University of Washington, Seattle, United States of America

3Weill Cornell Medicine, New York, United States of America

4Zenith Epigenetics, Calgary, Canada

5Triana Biomedicines, Waltham, United States of America

6Department of Epidemiology Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Chen, Y. in: PubMed | Google Scholar |

Published June 24, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI180378.
Copyright © 2025, Shukla et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 24, 2025 - Version history
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Abstract

A subgroup (~20-30%) of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by two GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlates with adverse clinical outcomes to androgen receptor signaling inhibitor treatment and shorter overall survival. Bromo- and extra-terminal domain inhibitors (BETi) downregulated HNF1A, HNF4G, and the GI transcriptome in multiple CRPC models, including cell lines, patient-derived organoids, and patient-derived xenografts, while 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.

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  • Version 1 (June 24, 2025): In-Press Preview
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