TY - UNPB
T1 - Enhancer profiling identifies epigenetic markers of endocrine resistance and reveals therapeutic options for metastatic castration-resistant prostate cancer patients
AU - Severson, Tesa M
AU - Zhu, Yanyun
AU - Prekovic, Stefan
AU - Schuurman, Karianne
AU - Nguyen, Holly M
AU - Brown, Lisha G
AU - Hakkola, Sini
AU - Kim, Yongsoo
AU - Kneppers, Jeroen
AU - Linder, Simon
AU - Stelloo, Suzan
AU - Lieftink, Cor
AU - van der Heijden, Michiel
AU - Nykter, Matti
AU - van der Noort, Vincent
AU - Sanders, Joyce
AU - Morris, Ben
AU - Jenster, Guido
AU - van Leenders, Geert Jlh
AU - Pomerantz, Mark
AU - Freedman, Matthew L
AU - Beijersbergen, Roderick L
AU - Urbanucci, Alfonso
AU - Wessels, Lodewyk
AU - Corey, Eva
AU - Zwart, Wilbert
AU - Bergman, Andries M
PY - 2023/2/24
Y1 - 2023/2/24
N2 - 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.
AB - 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.
U2 - 10.1101/2023.02.24.23286403
DO - 10.1101/2023.02.24.23286403
M3 - Preprint
C2 - 36865297
T3 - medRxiv
BT - Enhancer profiling identifies epigenetic markers of endocrine resistance and reveals therapeutic options for metastatic castration-resistant prostate cancer patients
ER -