title: Targeting MYCN in neuroblastoma by BET bromodomain inhibition.
abstract: Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis showed downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knockdown phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in 3 in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma.
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Alexandre
authors: A
authors: Puissant
authors: Stacey M
authors: SM
authors: Frumm
authors: Gabriela
authors: G
authors: Alexe
authors: Christopher F
authors: CF
authors: Bassil
authors: Jun
authors: J
authors: Qi
authors: Yvan H
authors: YH
authors: Chanthery
authors: Erin A
authors: EA
authors: Nekritz
authors: Rhamy
authors: R
authors: Zeid
authors: William Clay
authors: WC
authors: Gustafson
authors: Patricia
authors: P
authors: Greninger
authors: Matthew J
authors: MJ
authors: Garnett
authors: Ultan
authors: U
authors: McDermott
authors: Cyril H
authors: CH
authors: Benes
authors: Andrew L
authors: AL
authors: Kung
authors: William A
authors: WA
authors: Weiss
authors: James E
authors: JE
authors: Bradner
authors: Kimberly
authors: K
authors: Stegmaier
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001381:Azepines / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005784:Gene Amplification; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C489427:MYC protein, human; C459801:MYCN protein, human