title: BET Bromodomain Inhibitors Enhance Efficacy and Disrupt Resistance to AR Antagonists in the Treatment of Prostate Cancer.
abstract: 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.
  
  
  
  Therapeutic combinations of BET inhibitors and AR antagonists may enhance the clinical efficacy in the treatment of mCRPC.
  
  
  
  http://mcr.aacrjournals.org/content/molcanres/14/4/324/F1.large.jpg
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan. Department of Pathology, University of Michigan, Ann Arbor, Michigan. Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Irfan A
authors.initials: IA
authors.lastname: Asangani
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Kari
authors.initials: K
authors.lastname: Wilder-Romans
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Vijaya L
authors.initials: VL
authors.lastname: Dommeti
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Pranathi M
authors.initials: PM
authors.lastname: Krishnamurthy
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Apel
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: June
authors.initials: J
authors.lastname: Escara-Wilke
authors.affiliation: Department of Medicine, University of Washington and VAPSHCS, Seattle, Washington.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Plymate
authors.affiliation: Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Nora M
authors.initials: NM
authors.lastname: Navone
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan. Department of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan. Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan. Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan. Department of Pathology, University of Michigan, Ann Arbor, Michigan. Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan. Department of Urology, University of Michigan, Ann Arbor, Michigan. arul@umich.edu.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage* / Q000494:pharmacology; D059002:Androgen Receptor Antagonists / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D001381:Azepines / Q000008:administration & dosage* / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C561695:(+)-JQ1 compound; D000083:Acetanilides; D059002:Androgen Receptor Antagonists; D001381:Azepines; D001549:Benzamides; D006575:Heterocyclic Compounds, 3-Ring; D009570:Nitriles; C000605331:OTX015; D011944:Receptors, Androgen; D014230:Triazoles; D010669:Phenylthiohydantoin; C540278:enzalutamide