| First Author | Puissant A | Year | 2013 |
| Journal | Cancer Discov | Volume | 3 |
| Issue | 3 | Pages | 308-23 |
| PubMed ID | 23430699 | Mgi Jnum | J:198307 |
| Mgi Id | MGI:5496324 | Doi | 10.1158/2159-8290.CD-12-0418 |
| Citation | Puissant A, et al. (2013) Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov 3(3):308-23 |
| abstractText | 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. |
