title: BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells.
abstract: Uveal melanoma (UM) is an aggressive intraocular malignancy with limited therapeutic options. Both primary and metastatic UM are characterized by oncogenic mutations in the G-protein alpha subunit q and 11. Furthermore, nearly 40% of UM has amplification of the chromosomal arm 8q and monosomy of chromosome 3, with consequent anomalies of MYC copy number. Chromatin regulators have become attractive targets for cancer therapy. In particular, the bromodomain and extra-terminal (BET) inhibitor JQ1 has shown selective inhibition of c-Myc expression with antiproliferative activity in hematopoietic and solid tumors. Here we provide evidence that JQ1 had cytotoxic activity in UM cell lines carrying Gnaq/11 mutations, while in cells without the mutations had little effects. Using microarray analysis, we identified a large subset of genes modulated by JQ1 involved in the regulation of cell cycle, apoptosis and DNA repair. Further analysis of selected genes determined that the concomitant silencing of Bcl-xL and Rad51 represented the minimal requirement to mimic the apoptotic effects of JQ1 in the mutant cells, independently of c-Myc. In addition, administration of JQ1 to mouse xenograft models of Gnaq-mutant UM resulted in significant inhibition of tumor growth.Collectively, our results define BRD4 targeting as a novel therapeutic intervention against UM with Gnaq/Gna11 mutations.
authors.affiliation: The Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
authors.forename: Grazia
authors.initials: G
authors.lastname: Ambrosini
authors.affiliation: The Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Sawle
authors.affiliation: The Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
authors.forename: Elgilda
authors.initials: E
authors.lastname: Musi
authors.affiliation: The Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D001381:Azepines / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics*; D016259:Genes, myc / Q000502:physiology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D014230:Triazoles / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000098943:Uveal Melanoma; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D044385:GTP-Binding Protein alpha Subunits; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D009687:Nuclear Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C554062:GNA11 protein, human; C554061:GNAQ protein, human
keywords: BRD4; Bcl-xL; Gnaq/11; JQ1; Rad51