Enhancer profiling identifies epigenetic markers of endocrine resistance and reveals therapeutic options for metastatic castration-resistant prostate cancer patients

  • medRxiv. 2023 Feb 24:2023.02.24.23286403. doi: 10.1101/2023.02.24.23286403.
Tesa M Severson ,  Yanyun Zhu ,  Stefan Prekovic ,  Karianne Schuurman ,  Holly M Nguyen ,  Lisha G Brown ,  Sini Hakkola ,  Yongsoo Kim ,  Jeroen Kneppers ,  Simon Linder ,  Suzan Stelloo ,  Cor Lieftink ,  Michiel 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 ,  Eva Corey ,  Wilbert Zwart ,  Andries M Bergman
PMID: 36865297 DOI: 10.1101/2023.02.24.23286403
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 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.

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