期刊
CANCER DISCOVERY
卷 3, 期 3, 页码 308-323出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-12-0418
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资金
- V Foundation for Cancer Research Translational Grant
- Friends for Life Fellowship
- Howard Hughes Medical Institute Physician-Scientist Early Career Award
- Damon Runyon Cancer Research Foundation
- Smith Family Foundation
- Alex's Lemonade Stand
- NIH [R01CA102321, P01CA081403, K08NS079485, T32CA151022]
- Wellcome Trust [086357]
- Katie Dougherty Foundation
- Cancer League, Inc.
- Samuel Waxman Cancer Research Foundation
- L'Association pour la Recherche sur le Cancer
- Stand Up to Cancer Innovative Research Grant, a Program of the Entertainment Industry Foundation [SU2C-AACR-IRG0509]
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 signifi cant survival advantage in 3 in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. SIGNIFICANCE: Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anticancer activity, have been lacking. Here, we reveal MYCN 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 MYCN-amplified neuroblastoma. Cancer Discov; 3(3); 308-23. (C) 2012 AACR.
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