Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer

• Type of Material: Article
• Authors: Irfan A. Asangani, University of Michigan; Vijaya L. Dommeti, University of Michigan; Xiaoju Wang, University of Michigan; Rohit Malik, University of Michigan; Marcin Cieslik, University of Michigan; Rendong Yang, Emory University; June Escara-Wilke, University of Michigan; Kari Wilder-Romans, University of Michigan; Sudheer Dhanireddy, University of Michigan; Carl Engelke, University of Michigan; Mathew K. Iyer, University of Michigan; Xiaojun Jing, University of Michigan; Yi-Mi Wu, University of Michigan; Xuhong Cao, University of Michigan; Zhaohui Qin, Emory University; Shaomeng Wang, University of Michigan; Felix Y. Feng, University of Michigan; Arul M. Chinnaiyan, University of Michigan
• Language: English
• Date: 2014-06-12
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Macmillan Publishers Limited.
• Final Published Version (URL): http://dx.doi.org/10.1038/nature13229
• Title of Journal or Parent Work: Nature
• ISSN: 0028-0836
• Volume: 510
• Issue: 7504
• Start Page: 278
• End Page: +
• Grant/Funding Information: This work was supported by Challenge Grant from the Prostate Cancer Foundation (PCF); and in part by the Early Detection Research Network (UO1 CA111275); and the NCI Prostate SPORE (P50CA69568) to A.M.C.; A.M.C. is also supported by the Doris Duke Charitable Foundation; American Cancer Society; and A. Alfred-Taubman Institute.; I.A.A. is supported by a PCF Young Investigator Award.
• Keywords: INCREASED SURVIVAL; Multidisciplinary Sciences; Science & Technology - Other Topics; ABIRATERONE; GENE; RECRUITMENT; P-TEFB; ANTIANDROGEN; BRD4; Science & Technology; SELECTIVE-INHIBITION; CHIP-SEQ; TRANSCRIPTION
• Research Categories: Biology, Biostatistics; Health Sciences, Oncology; Health Sciences, Pathology

Abstract

Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. Progression to CRPC after androgen ablation therapy is predominantly driven by deregulated androgen receptor (AR) signalling. Despite the success of recently approved therapies targeting AR signalling, such as abiraterone and second-generation anti-androgens including MDV3100 (also known as enzalutamide), durable responses are limited, presumably owing to acquired resistance. Recently, JQ1 and I-BET762 two selective small-molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit anti-proliferative effects in a range of malignancies. Here we show that AR-signalling-competent human CRPC cell lines are preferentially sensitive to bromodomain and extraterminal (BET) inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1 (refs 11, 13). Like the direct AR antagonist MDV3100, JQ1 disrupted AR recruitment to target gene loci. By contrast with MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR-mediated gene transcription, including induction of the TMPRSS2-ERG gene fusion and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft mouse models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer.