Publication Date:
2014-04-25
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075966/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075966/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Asangani, Irfan A -- Dommeti, Vijaya L -- Wang, Xiaoju -- Malik, Rohit -- Cieslik, Marcin -- Yang, Rendong -- Escara-Wilke, June -- Wilder-Romans, Kari -- Dhanireddy, Sudheer -- Engelke, Carl -- Iyer, Mathew K -- Jing, Xiaojun -- Wu, Yi-Mi -- Cao, Xuhong -- Qin, Zhaohui S -- Wang, Shaomeng -- Feng, Felix Y -- Chinnaiyan, Arul M -- P50 CA069568/CA/NCI NIH HHS/ -- P50CA69568/CA/NCI NIH HHS/ -- T32 GM007863/GM/NIGMS NIH HHS/ -- U01 CA111275/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jun 12;510(7504):278-82. doi: 10.1038/nature13229. Epub 2014 Apr 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia 30329, USA. ; Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; 1] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; 1] Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; 1] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [3] Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; 1] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [3] Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [4] Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [5] Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24759320" target="_blank"〉PubMed〈/a〉
Keywords:
Androgen Antagonists/pharmacology
;
Androgens/metabolism
;
Animals
;
Azepines/*pharmacology/therapeutic use
;
Cell Line, Tumor
;
Disease Models, Animal
;
Epigenesis, Genetic
;
Humans
;
Male
;
Mice
;
Nuclear Proteins/*chemistry
;
Oncogene Proteins, Fusion/genetics/metabolism
;
Prostatic Neoplasms, Castration-Resistant/*drug therapy/genetics
;
Protein Structure, Tertiary/drug effects
;
Receptors, Androgen/chemistry/metabolism
;
Signal Transduction/drug effects
;
Transcription Factors/*chemistry
;
Triazoles/*pharmacology/therapeutic use
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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