JOURNAL ARTICLE

Targeting MYCN in neuroblastoma by BET bromodomain inhibition

Alexandre Puissant, Stacey M Frumm, Gabriela Alexe, Christopher F Bassil, Jun Qi, Yvan H Chanthery, Erin A Nekritz, Rhamy Zeid, William Clay Gustafson, Patricia Greninger, Matthew J Garnett, Ultan McDermott, Cyril H Benes, Andrew L Kung, William A Weiss, James E Bradner, Kimberly Stegmaier
Cancer Discovery 2013, 3 (3): 308-23
23430699
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.

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