Epigenetic profiling identifies markers of endocrine resistance and therapeutic options for metastatic castration-resistant prostate cancer
Tesa Severson, Emma Minnee, Yanyun Zhu, Karianne Schuurman, Holly M. Nguyen, Lisha G. Brown, Sini Hakkola, Renée X. de 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 M. Pomerantz, Matthew L. Freedman, Roderick L. Beijersbergen, Alfonso Urbanucci, Lodewyk F.A. Wessels, Peter S. Nelson, Eva Corey, Stefan Preković, Wilbert Zwart, Andries M. Bergman
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.