Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Puissant, A, Frumm, SM, Alexe, G, Bassil, CF, Qi, J, Chanthery, YH, Nekritz, EA, Zeid, R, Gustafson, WClay, Greninger, P, Garnett, MJ, McDermott, U, Benes, CH, Kung, AL, Weiss, WA, Bradner, JE, Stegmaier, K |
Journal | Cancer Discov |
Volume | 3 |
Issue | 3 |
Pages | 308-23 |
Date Published | 2013 Mar |
ISSN | 2159-8290 |
Keywords | Animals, Apoptosis, Azepines, Cell Cycle Checkpoints, Cell Growth Processes, Cell Line, Tumor, Child, Down-Regulation, Female, Gene Amplification, Humans, Mice, Molecular Targeted Therapy, N-Myc Proto-Oncogene Protein, Neuroblastoma, Nuclear Proteins, Oncogene Proteins, Promoter Regions, Genetic, Protein Structure, Tertiary, Proto-Oncogene Proteins c-myc, RNA, Small Interfering, Transcription Factors, Transfection, Triazoles, Xenograft Model Antitumor Assays |
Abstract | 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. |
URL | http://cancerdiscovery.aacrjournals.org/cgi/pmidlookup?view=long&pmid=23430699 |
DOI | 10.1158/2159-8290.CD-12-0418 |
Pubmed | |
Alternate Journal | Cancer Discov |
PubMed ID | 23430699 |
PubMed Central ID | PMC3672953 |
Grant List | K08 NS079485 / NS / NINDS NIH HHS / United States R01 CA102321 / CA / NCI NIH HHS / United States T32 CA151022 / CA / NCI NIH HHS / United States 093868 / / Wellcome Trust / United Kingdom P01 CA081403 / CA / NCI NIH HHS / United States P01CA081403 / CA / NCI NIH HHS / United States K08NS079485 / NS / NINDS NIH HHS / United States 086357 / / Wellcome Trust / United Kingdom T32CA151022 / CA / NCI NIH HHS / United States R01CA102321 / CA / NCI NIH HHS / United States T32 CA128583 / CA / NCI NIH HHS / United States |
Cancer Discov DOI:10.1158/2159-8290.CD-12-0418
Targeting MYCN in neuroblastoma by BET bromodomain inhibition.
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