Data from Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition

Abstract

<div>Abstract<p>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 <i>MYCN</i> 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 <i>MYCN</i>. Genome-wide expression analysis showed downregulation of the MYCN transcriptional program accompanied by suppression of <i>MYCN</i> 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 <i>MYCN</i>. BET inhibition conferred a significant survival advantage in 3 <i>in vivo</i> neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma.</p><p><b>Significance:</b> Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anticancer activity, have been lacking. Here, we reveal <i>MYCN</i> amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, show a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with <i>MYCN</i>-amplified neuroblastoma. <i>Cancer Discov; 3(3); 308–23. ©2012 AACR.</i></p><p>See related commentary by Schnepp and Maris, p. 255</p><p>This article is highlighted in the In This Issue feature, p. 239</p></div>