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Cancer Discov DOI:10.1158/2159-8290.CD-12-0418

Targeting MYCN in neuroblastoma by BET bromodomain inhibition.

Publication TypeJournal Article
Year of Publication2013
AuthorsPuissant, 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
JournalCancer Discov
Volume3
Issue3
Pages308-23
Date Published2013 Mar
ISSN2159-8290
KeywordsAnimals, 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.

URLhttp://cancerdiscovery.aacrjournals.org/cgi/pmidlookup?view=long&pmid=23430699
DOI10.1158/2159-8290.CD-12-0418
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23430699?dopt=Abstract

Alternate JournalCancer Discov
PubMed ID23430699
PubMed Central IDPMC3672953
Grant ListK08 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