title: Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer.
abstract: BET (bromodomain and extra-terminal) proteins regulate gene expression through their ability to bind to acetylated chromatin and subsequently activate RNA PolII-driven transcriptional elongation. Small molecule BET inhibitors prevent binding of BET proteins to acetylated histones and inhibit transcriptional activation of BET target genes. BET inhibitors attenuate cell growth and survival in several hematologic cancer models, partially through the down-regulation of the critical oncogene, MYC. We hypothesized that BET inhibitors will regulate MYC expression in solid tumors that frequently over-express MYC. Here we describe the effects of the highly specific BET inhibitor, I-BET762, on MYC expression in prostate cancer models. I-BET762 potently reduced MYC expression in prostate cancer cell lines and a patient-derived tumor model with subsequent inhibition of cell growth and reduction of tumor burden in vivo. Our data suggests that I-BET762 effects are partially driven by MYC down-regulation and underlines the critical importance of additional mechanisms of I-BET762 induced phenotypes.
authors.affiliation: Cancer Epigenetics DPU, Oncology R and D GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Wyce
authors.forename: Yan
authors.initials: Y
authors.lastname: Degenhardt
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Bai
authors.forename: BaoChau
authors.initials: B
authors.lastname: Le
authors.forename: Susan
authors.initials: S
authors.lastname: Korenchuk
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Crouthame
authors.forename: Charles F
authors.initials: CF
authors.lastname: McHugh
authors.forename: Robert
authors.initials: R
authors.lastname: Vessella
authors.forename: Caretha L
authors.initials: CL
authors.lastname: Creasy
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tummino
authors.forename: Olena
authors.initials: O
authors.lastname: Barbash
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D009687:Nuclear Proteins; D001569:Benzodiazepines; C554645:molibresib; D017346:Protein Serine-Threonine Kinases