title: BET inhibition silences expression of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models.
abstract: BET family proteins are epigenetic regulators known to control expression of genes involved in cell growth and oncogenesis. Selective inhibitors of BET proteins exhibit potent anti-proliferative activity in a number of hematologic cancer models, in part through suppression of the MYC oncogene and downstream Myc-driven pathways. However, little is currently known about the activity of BET inhibitors in solid tumor models, and whether down-regulation of MYC family genes contributes to sensitivity. Here we provide evidence for potent BET inhibitor activity in neuroblastoma, a pediatric solid tumor associated with a high frequency of MYCN amplifications. We treated a panel of neuroblastoma cell lines with a novel small molecule inhibitor of BET proteins, GSK1324726A (I-BET726), and observed potent growth inhibition and cytotoxicity in most cell lines irrespective of MYCN copy number or expression level. Gene expression analyses in neuroblastoma cell lines suggest a role of BET inhibition in apoptosis, signaling, and N-Myc-driven pathways, including the direct suppression of BCL2 and MYCN. Reversal of MYCN or BCL2 suppression reduces the potency of I-BET726-induced cytotoxicity in a cell line-specific manner; however, neither factor fully accounts for I-BET726 sensitivity. Oral administration of I-BET726 to mouse xenograft models of human neuroblastoma results in tumor growth inhibition and down-regulation MYCN and BCL2 expression, suggesting a potential role for these genes in tumor growth. Taken together, our data highlight the potential of BET inhibitors as novel therapeutics for neuroblastoma, and suggest that sensitivity is driven by pleiotropic effects on cell growth and apoptotic pathways in a context-specific manner.
authors.affiliation: Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Wyce
authors.forename: Gopinath
authors.initials: G
authors.lastname: Ganji
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: Smitheman
authors.forename: Chun-Wa
authors.initials: CW
authors.lastname: Chung
authors.forename: Susan
authors.initials: S
authors.lastname: Korenchuk
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Bai
authors.forename: Olena
authors.initials: O
authors.lastname: Barbash
authors.forename: BaoChau
authors.initials: B
authors.lastname: Le
authors.forename: Peter D
authors.initials: PD
authors.lastname: Craggs
authors.forename: Michael T
authors.initials: MT
authors.lastname: McCabe
authors.forename: Karen M
authors.initials: KM
authors.lastname: Kennedy-Wilson
authors.forename: Lydia V
authors.initials: LV
authors.lastname: Sanchez
authors.forename: Romain L
authors.initials: RL
authors.lastname: Gosmini
authors.forename: Nigel
authors.initials: N
authors.lastname: Parr
authors.forename: Charles F
authors.initials: CF
authors.lastname: McHugh
authors.forename: Dashyant
authors.initials: D
authors.lastname: Dhanak
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Auger
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tummino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D006801:Humans; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001569:Benzodiazepines; D018797:Cell Cycle Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C109106:BRD3 protein, human; C441289:BRD4 protein, human; C109570:BRDT protein, human; C459801:MYCN protein, human; C554645:molibresib