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

Irfan A. Asangani, Vijaya L. Dommeti, Xiaoju Wang, Rohit Malik, Marcin Cieslik, Rendong Yang, June Escara-Wilke, Kari Wilder-Romans, Sudheer Dhanireddy, Carl Engelke, Mathew K. Iyer, Xiaojun Jing, Yi Mi Wu, Xuhong Cao, Zhaohui S. Qin, Shaomeng Wang, Felix Y. Feng, Arul M. Chinnaiyan

Research output: Contribution to journalArticlepeer-review

585 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)278-282
Number of pages5
JournalNature
Volume510
Issue number7504
DOIs
StatePublished - 2014
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgements We thank A. Paliakov, T. Barrette, Y. Qiao, P. Vats, R. Stender, X. Jiang, M. Pranithi and S. Han for technical assistance; C. Kumar-Sinha, M. Dhanasekaran, N. Palanisamy and P. Kunju for helpful discussions; J. Athanikar and K. Giles for critically reading the manuscript and submission of documents. This work was supported by a Movember-Prostate Cancer Foundation Challenge Award 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. and R.A. are supported by a PCF Young Investigator Award.

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