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Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition.

Publication TypeJournal Article
AuthorsPuissant, A., Frumm SM, Alexe G., Bassil CF, Qi J., Chanthery YH, Nekritz EA, Zeid R., Gustafson WC, Greninger P., Garnett MJ, McDermott U., Benes CH, Kung AL, Weiss WA, Bradner JE, and Stegmaier K.
AbstractBromodomain 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.
Year of Publication2013
JournalCancer discovery
Volume3
Issue3
Pages308-323
Date Published (YYYY/MM/DD)2013/03/01
ISSN Number2159-8274
DOI10.1158/2159-8290.CD-12-0418
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/23430699?dopt=Abstract