BET Bromodomain Inhibitors Enhance Efficacy and Disrupt Resistance to AR Antagonists in the Treatment of Prostate Cancer

• Published in: Molecular cancer research Vol. 14; no. 4; pp. 324 - 331
• Main Authors: Asangani, Irfan A., Wilder-Romans, Kari, Dommeti, Vijaya L., Krishnamurthy, Pranathi M., Apel, Ingrid J., Escara-Wilke, June, Plymate, Stephen R., Navone, Nora M., Wang, Shaomeng, Feng, Felix Y., Chinnaiyan, Arul M.
• Format: Journal Article
• Language: English
• Published: United States 01.04.2016
• Subjects: Acetanilides - administration & dosage; Acetanilides - pharmacology; Androgen Receptor Antagonists - administration & dosage; Androgen Receptor Antagonists - pharmacology; Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Azepines - administration & dosage; Azepines - pharmacology; Benzamides; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Drug Resistance, Neoplasm - drug effects; Heterocyclic Compounds, 3-Ring - administration & dosage; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Male; Mice; Nitriles; Phenylthiohydantoin - administration & dosage; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - metabolism; Receptors, Androgen - metabolism; Signal Transduction - drug effects; Triazoles - administration & dosage; Triazoles - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 1541-7786; 1557-3125; 1557-3125
• DOI: 10.1158/1541-7786.MCR-15-0472

Next-generation antiandrogen therapies, such as enzalutamide and abiraterone, have had a profound impact on the management of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC patients invariably develop resistance to these agents. Here, a series of clonal cell lines were developed from enzalutamide-resistant prostate tumor xenografts to study the molecular mechanism of resistance and test their oncogenic potential under various treatment conditions. Androgen receptor (AR) signaling was maintained in these cell lines, which acquired potential resistance mechanisms, including expression of AR-variant 7 (AR-v7) and glucocorticoid receptor. BET bromodomain inhibitors were shown previously to attenuate AR signaling in mCRPC; here, we demonstrate the efficacy of bromodomain and extraterminal (BET) inhibitors in enzalutamide-resistant prostate cancer models. AR antagonists, enzalutamide, and ARN509 exhibit enhanced prostate tumor growth inhibition when combined with BET inhibitors, JQ1 and OTX015, respectively. Taken together, these data provide a compelling preclinical rationale to combine BET inhibitors with AR antagonists to subvert resistance mechanisms. Implications: Therapeutic combinations of BET inhibitors and AR antagonists may enhance the clinical efficacy in the treatment of mCRPC. Visual Overview: http://mcr.aacrjournals.org/content/14/4/324/F1.large.jpg. Mol Cancer Res; 14(4); 324–31. ©2016 AACR.