Epigenetic profiling identifies markers of endocrine resistance and therapeutic options for metastatic castration-resistant prostate cancer

  • Cell Rep Med. 2025 Jul 15;6(7):102215. doi: 10.1016/j.xcrm.2025.102215.
Tesa M Severson  1 ,  Emma Minnee  2 ,  Yanyun Zhu  2 ,  Karianne Schuurman  3 ,  Holly M Nguyen  4 ,  Lisha G Brown  4 ,  Sini Hakkola  5 ,  Renee Menezes  6 ,  Sebastian Gregoricchio  2 ,  Yongsoo Kim  3 ,  Jeroen Kneppers  2 ,  Simon Linder  2 ,  Suzan Stelloo  2 ,  Cor Lieftink  7 ,  Michiel S van der Heijden  8 ,  Matti Nykter  5 ,  Vincent van der Noort  9 ,  Joyce Sanders  10 ,  Ben Morris  7 ,  Guido Jenster  11 ,  Geert Jlh van Leenders  12 ,  Mark Pomerantz  13 ,  Matthew L Freedman  14 ,  Roderick L Beijersbergen  7 ,  Alfonso Urbanucci  15 ,  Lodewyk Wessels  16 ,  Peter S Nelson  17 ,  Eva Corey  4 ,  Stefan Prekovic  2 ,  Wilbert Zwart  18 ,  Andries M Bergman  19
Affiliations
  • 1. Division of Oncogenomics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, 3584 CG Utrecht, the Netherlands; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
  • 2. Division of Oncogenomics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, 3584 CG Utrecht, the Netherlands.
  • 3. Division of Oncogenomics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
  • 4. Department of Urology, University of Washington, Seattle, WA 98195, USA.
  • 5. Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, 33100 Tampere, Finland.
  • 6. Biostatistics Centre & Department of Psychosocial Research and Epidemiology, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
  • 7. Division of Molecular Carcinogenesis and NKI Robotics and Screening Center, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
  • 8. Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Division of Medical Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
  • 9. Department of Biometrics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
  • 10. Department of Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
  • 11. Department of Urology, Erasmus MC, 3015 GD Rotterdam, the Netherlands.
  • 12. Department of Pathology, Erasmus MC Cancer Institute, 3015 CP Rotterdam, the Netherlands.
  • 13. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 14. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA.
  • 15. Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, 33100 Tampere, Finland; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.
  • 16. Cancer Genomics Netherlands, Oncode Institute, 3584 CG Utrecht, the Netherlands; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Department of EEMCS, Delft University of Technology, 2628 CM Delft, the Netherlands.
  • 17. Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA 98195, USA.
  • 18. Division of Oncogenomics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, 3584 CG Utrecht, the Netherlands; Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, the Netherlands. Electronic address: [email protected].
  • 19. Division of Oncogenomics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Division of Medical Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands. Electronic address: [email protected].
PMID: 40609538 DOI: 10.1016/j.xcrm.2025.102215
Abstract

Androgen Receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate Cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase 2 clinical trial, we epigenetically profile enhancer/promoter activities with acetylation of lysine residue 27 on histone 3 (H3K27ac) chromatin immunoprecipitation followed by Sequencing, before and after AR-targeted therapy. We identify a distinct subset of H3K27ac-differentially marked regions that are associated with treatment responsiveness, which we successfully validate in mCRPC patient-derived xenograft (PDX) models. In silico analyses reveal histone deacetylase (HDAC)3 to critically drive resistance to hormonal interventions, which we validate in vitro. Critically, we identify the pan-HDAC inhibitor vorinostat to be effective in decreasing tumor cell proliferation, both in vitro and in vivo. Moreover, we uncover evidence for HDAC3 working together with Glucocorticoid Receptor (GR) as a potential mechanism for this therapeutic effect. These findings demonstrate the rationale for therapeutic strategies including HDAC inhibitors to improve patient outcome in advanced stages of mCRPC.

Keywords
H3K27ac; HDAC inhibitors; androgen receptor; biomarkers; drug resistance; enzalutamide; epigenetics; hormone intervention; mCRPC; prostate cancer.
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