Author:
Severson Tesa M.,Zhu Yanyun,Prekovic Stefan,Schuurman Karianne,Nguyen Holly M.,Brown Lisha G.,Hakkola Sini,Kim Yongsoo,Kneppers Jeroen,Linder Simon,Stelloo Suzan,Lieftink Cor,van der Heijden Michiel,Nykter Matti,van der Noort Vincent,Sanders Joyce,Morris Ben,Jenster Guido,van Leenders Geert JLH,Pomerantz Mark,Freedman Matthew L.,Beijersbergen Roderick L.,Urbanucci Alfonso,Wessels Lodewyk,Corey Eva,Zwart Wilbert,Bergman Andries M.
Abstract
AbstractAndrogen 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 silicoanalyses revealed HDAC3 as a critical factor that can drive resistance to hormonal interventions, which we validatedin vitro. Using cell lines and mCRPC PDX tumorsin 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.
Publisher
Cold Spring Harbor Laboratory