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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Azepines / pharmacology
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Cell Cycle Checkpoints / drug effects
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Cell Cycle Checkpoints / genetics
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Cell Cycle Proteins
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Cell Growth Processes / genetics
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Cell Line, Tumor
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Child
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Down-Regulation / drug effects
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Female
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Gene Amplification
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Humans
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Mice
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Molecular Targeted Therapy
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N-Myc Proto-Oncogene Protein
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Neuroblastoma / drug therapy*
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Neuroblastoma / genetics
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Neuroblastoma / metabolism
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Neuroblastoma / pathology
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism*
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Oncogene Proteins / genetics*
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Oncogene Proteins / metabolism
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Promoter Regions, Genetic
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-myc / genetics
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RNA, Small Interfering / administration & dosage
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RNA, Small Interfering / genetics
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transfection
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Triazoles / pharmacology
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Xenograft Model Antitumor Assays
Substances
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(+)-JQ1 compound
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Azepines
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BRD4 protein, human
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Cell Cycle Proteins
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MYC protein, human
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MYCN protein, human
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N-Myc Proto-Oncogene Protein
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Nuclear Proteins
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Oncogene Proteins
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Proto-Oncogene Proteins c-myc
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RNA, Small Interfering
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Transcription Factors
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Triazoles