Enhancer Profiling Identifies Epigenetic Markers of Endocrine Resistance and Reveals Therapeutic Options for Metastatic Castration-Resistant Prostate Cancer Patients
Netherlands Cancer Institute - Division of Oncogenomics; Oncode Institute; Radboud University Nijmegen - Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute
Tampere University - Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tays Cancer Centre; University of Oslo - Department of Tumor Biology, Institute for Cancer Research
Netherlands Cancer Institute - Division of Molecular Carcinogenesis; Delft University of Technology - Department of Engineering, Mathematics and Computer Science (EEMCS); Oncode Institute
Netherlands Cancer Institute - Division of Oncogenomics; Oncode Institute; Eindhoven University of Technology (TUE) - Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering
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 II clinical trial, we epigenetically profiled enhancer/promoter activities with H3K27ac chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identified a distinct subset of H3K27ac-differentially marked regions that associated with treatment responsiveness. These data were successfully validated in mCRPC patient-derived xenograft models (PDX). In silico analyses revealed HDAC3 as a critical factor that can drive resistance to hormonal interventions, which we validated in vitro. Using cell lines and mCRPC PDX tumors in vitro, we identified drug-drug synergy between enzalutamide and the pan-HDAC inhibitor vorinostat, providing therapeutic proof-of-concept. These findings demonstrate rationale for new therapeutic strategies using a combination of AR and HDAC inhibitors to improve patient outcome in advanced stages of mCRPC.
Note:
Trial Registration Details: This single center cohort study was conducted as a sub-investigation of the CPCT-02 biopsy protocol (NCT01855477).
Funding Information: This work is supported by Astellas Pharma Europe BV (WZ, AMB), The Prostate Cancer Foundation (Challenge Award – MLF, MMP, WZ, TMS); The United States Department of Defense (Idea Award, PC180367 – MLF, MMP, WZ); Oncode Institute (WZ), KWF Dutch Cancer Society / Alpe d’HuZes (10084 – WZ, AMB and 7080 – AMB, MSvdH, LW), PNW Prostate Cancer SPORE (P50CA097186, P01CA163227 – EC) and Craig Watjen Memorial funds (EC); Academy of Finland (#349314 – AU) and Norwegian Cancer Society (#198016-2018 – AU); S. H. and M.N. Academy of Finland (#312043, #310829).
Declaration of Interests: WZ and AMB received research funding from Astellas Pharma for the work performed in this manuscript. All other authors declare no competing interests.
Ethics Approval Statement: This study was approved by the local medical ethics committee of the Netherlands Cancer Institute and was activated on January 24th, 2012. The protocol complied with the ethical principles of the Declaration of Helsinki. Patients provided signed informed consent for translational studies and recording and analysis of baseline characteristics and clinical outcomes of ENZA treatment. All animal experiments were performed after University of Washington IACUC approval following ARRIVE and NIH guidelines
Severson, Tesa M. and Zhu, Yanyun and Prekovic, Stefan and Schuurman, Karianne and Nguyen, Holly M. and Brown, Lisha G. and Hakkola, Sini and Kim, Yongsoo and Kneppers, Jeroen and Linder, Simon and Stelloo, Suzan and Lieftink, Cor and van der Heijden, Michiel S. and Nykter, Matti and van der Noort, Vincent and Sanders, Joyce and Morris, Ben and Jenster, Guido and van Leenders, Geert JLH and Pomerantz, Mark and Freedman, Matthew L. and Beijersbergen, Roderick and Urbanucci, Alfonso and Wessels, Lodewyk and Corey, Eva and Zwart, Wilbert and Bergman, Andries M., Enhancer Profiling Identifies Epigenetic Markers of Endocrine Resistance and Reveals Therapeutic Options for Metastatic Castration-Resistant Prostate Cancer Patients. Available at SSRN: https://ssrn.com/abstract=4382773 or http://dx.doi.org/10.2139/ssrn.4382773
This version of the paper has not been formally peer reviewed.
Radboud University Nijmegen - Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute ( email )
Eindhoven University of Technology (TUE) - Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering ( email )
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