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

Tesa M Severson; Emma Minnee; Yanyun Zhu; Karianne Schuurman; Holly M Nguyen; Lisha G Brown; Sini Hakkola; Renee Menezes; Sebastian Gregoricchio; Yongsoo Kim; Jeroen Kneppers; Simon Linder; Suzan Stelloo; Cor Lieftink; Michiel S van der Heijden; Matti Nykter; Vincent van der Noort; Joyce Sanders; Ben Morris; Guido Jenster; Geert Jlh van Leenders; Mark Pomerantz; Matthew L Freedman; Roderick L Beijersbergen; Alfonso Urbanucci; Lodewyk Wessels; Peter S Nelson; Eva Corey; Stefan Prekovic; Wilbert Zwart; Andries M Bergman

doi:10.1016/j.xcrm.2025.102215

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

Cell Rep Med. 2025 Jun 27:102215. doi: 10.1016/j.xcrm.2025.102215. Online ahead of print.

Authors

Tesa M Severson¹, Emma Minnee², Yanyun Zhu², Karianne Schuurman³, Holly M Nguyen⁴, Lisha G Brown⁴, Sini Hakkola⁵, Renee Menezes⁶, Sebastian Gregoricchio², Yongsoo Kim³, Jeroen Kneppers², Simon Linder², Suzan Stelloo², Cor Lieftink⁷, Michiel S van der Heijden⁸, Matti Nykter⁵, Vincent van der Noort⁹, Joyce Sanders¹⁰, Ben Morris⁷, Guido Jenster¹¹, Geert Jlh van Leenders¹², Mark Pomerantz¹³, Matthew L Freedman¹⁴, Roderick L Beijersbergen⁷, Alfonso Urbanucci¹⁵, Lodewyk Wessels¹⁶, Peter S Nelson¹⁷, Eva Corey⁴, Stefan Prekovic², Wilbert Zwart¹⁸, Andries M Bergman¹⁹

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: w.zwart@nki.nl.
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: a.bergman@nki.nl.

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.