Journal Article

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

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

2014

Overview

Small-molecule compounds that target the BET domain in proteins such as BRD4 have recently been identified as potential anticancer agents; here, the efficacy of the BRD4-targeting compound JQ1 is demonstrated in castration-resistant prostate cancer driven by deregulated androgen receptor action. Targeting castration-resistant prostate cancer Small-molecule compounds that target the BET domain chromatin factors such as BRD4 have recently come to the fore as potential anticancer agents in several cancer types. Arul Chinnaiyan and colleagues now demonstrate efficacy of the BRD4-targeting compound JQ1 in castration-resistant prostate cancer driven by deregulated androgen receptor action. They see inhibition of tumour xenograft growth in vivo in a mouse model through a mechanism that appears to endow JQ1 with greater potency than classical androgen receptor antagonists. Castration can control some prostate cancers by reducing levels of male sex hormone levels but tumours can become resistant. The prognosis for castration-resistant prostate cancers is generally poor. This work identifies the targeting of co-activators or mediators of androgen receptor transcriptional signalling as a possible alternative therapeutic strategy. 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 1 , 2 , 3 . Despite the success of recently approved therapies targeting AR signalling, such as abiraterone 4 , 5 , 6 and second-generation anti-androgens including MDV3100 (also known as enzalutamide) 7 , 8 , 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 9 , 10 , 11 , 12 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67 / Androgen Antagonists - pharmacology / Androgens - metabolism / Animals / Azepines - pharmacology / Azepines - therapeutic use / Cancer / Care and treatment / Cell Cycle Proteins / Cell growth / Cell Line, Tumor / Complications and side effects / Development and progression / Disease Models, Animal / Drug targeting / Epigenesis, Genetic / Gene expression / Genomes / Health aspects / Humanities and Social Sciences / Humans / letter / Male / Metastasis / Mice / multidisciplinary / Nuclear Proteins - chemistry / Oncogene Proteins, Fusion - genetics / Oncogene Proteins, Fusion - metabolism / Oncology, Experimental / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - drug therapy / Prostatic Neoplasms, Castration-Resistant - genetics / Protein Structure, Tertiary - drug effects / Proteins / Receptors, Androgen - chemistry / Receptors, Androgen - metabolism / RNA polymerase / Rodents / Science / Signal Transduction - drug effects / Transcription factors / Transcription Factors - chemistry / Triazoles - pharmacology / Triazoles - therapeutic use