title: Exploitation of Castration-Resistant Prostate Cancer Transcription Factor Dependencies by the Novel BET Inhibitor ABBV-075.
abstract: Competitive inhibitors of acetyl-lysine binding to the bromodomains of the BET (bromodomain and extra terminal) family are being developed for the treatment of solid and hematologic malignancies. The function of BET family member BRD4 at enhancers/superenhancers has been shown to sustain signal-dependent or pathogenic gene expression programs. Here, the hypothesis was tested that the transcription factor drivers of castration-resistant prostate cancer (CRPC) clinical progression, including the androgen receptor (AR), are critically dependent on BRD4 and thus represent a sensitive solid tumor indication for the BET inhibitor ABBV-075. DHT-stimulated transcription of AR target genes was inhibited by ABBV-075 without significant effect on AR protein expression. Furthermore, ABBV-075 disrupted DHT-stimulated recruitment of BET family member BRD4 to gene-regulatory regions cooccupied by AR, including the well-established PSA and TMPRSS2 enhancers. Persistent BET inhibition disrupted the composition and function of AR-occupied enhancers as measured by a reduction in AR and H3K27Ac ChIP signal and inhibition of enhancer RNA transcription. ABBV-075 displayed potent antiproliferative activity in multiple models of resistance to second-generation antiandrogens and inhibited the activity of the AR splice variant AR-V7 and ligand-binding domain gain-of-function mutations, F877L and L702H. ABBV-075 was also a potent inhibitor of MYC and the TMPRSS2-ETS fusion protein, important parallel transcription factor drivers of CRPC.
  
  
  
  The ability of BET family inhibitor ABBV-075 to inhibit transcription activation downstream of the initiating events of transcription factors like AR and TMPRSS2:ETS fusion proteins provides a promising therapeutic option for CRPC patients who have developed resistance to second-generation antiandrogens. Mol Cancer Res; 15(1); 35-44. ©2016 AACR.
authors.affiliation: AbbVie Inc., North Chicago, Illinois. emily.faivre@abbvie.com yu.shen@abbvie.com.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Faivre
authors.affiliation: AbbVie Inc., North Chicago, Illinois.
authors.forename: Denise
authors.initials: D
authors.lastname: Wilcox
authors.affiliation: AbbVie Inc., North Chicago, Illinois.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Lin
authors.affiliation: AbbVie Inc., North Chicago, Illinois.
authors.forename: Paul
authors.initials: P
authors.lastname: Hessler
authors.affiliation: AbbVie Inc., North Chicago, Illinois.
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
authors.affiliation: AbbVie Inc., North Chicago, Illinois.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: AbbVie Inc., North Chicago, Illinois.
authors.forename: Tamar
authors.initials: T
authors.lastname: Uziel
authors.affiliation: AbbVie Inc., North Chicago, Illinois.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.affiliation: AbbVie Inc., North Chicago, Illinois.
authors.forename: Keith
authors.initials: K
authors.lastname: McDaniel
authors.affiliation: AbbVie Inc., North Chicago, Illinois.
authors.forename: Warren
authors.initials: W
authors.lastname: Kati
authors.affiliation: AbbVie Inc., North Chicago, Illinois. emily.faivre@abbvie.com yu.shen@abbvie.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004742:Enhancer Elements, Genetic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008297:Male; D051379:Mice; D009570:Nitriles; D010641:Phenotype; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000473:pathology*; D000072417:Protein Domains; D011728:Pyridones / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D001549:Benzamides; D002843:Chromatin; D008024:Ligands; D009570:Nitriles; D011728:Pyridones; D011944:Receptors, Androgen; D013449:Sulfonamides; D014157:Transcription Factors; D013196:Dihydrotestosterone; D010669:Phenylthiohydantoin; C540278:enzalutamide; C000621792:mivebresib