Targeting MYCN in neuroblastoma by BET bromodomain inhibition.
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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. |
Year of Publication | 2013
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Journal | Cancer Discov
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Volume | 3
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Issue | 3
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Pages | 308-23
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Date Published | 2013 Mar
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ISSN | 2159-8290
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URL | |
DOI | 10.1158/2159-8290.CD-12-0418
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PubMed ID | 23430699
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PubMed Central ID | PMC3672953
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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
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