Cancer discovery, 2013-03, Vol.3 (3), p.308-323
2013
Details
- Autor(en) / Beteiligte
- Titel
- Targeting MYCN in neuroblastoma by BET bromodomain inhibition
- Ist Teil von
- Cancer discovery, 2013-03, Vol.3 (3), p.308-323
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2013
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2159-8274eISSN: 2159-8290DOI: 10.1158/2159-8290.cd-12-0418Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3672953
- Format
- –
- Schlagworte
- Animals, Apoptosis - drug effects, Apoptosis - genetics, Azepines - pharmacology, Cell Cycle Checkpoints - drug effects, Cell Cycle Checkpoints - genetics, Cell Growth Processes - genetics, Cell Line, Tumor, Child, Down-Regulation - drug effects, Female, Gene Amplification, Humans, Mice, Molecular Targeted Therapy, N-Myc Proto-Oncogene Protein, Neuroblastoma - drug therapy, Neuroblastoma - genetics, Neuroblastoma - metabolism, Neuroblastoma - pathology, Nuclear Proteins - antagonists & inhibitors, Nuclear Proteins - deficiency, Nuclear Proteins - genetics, Nuclear Proteins - metabolism, Oncogene Proteins - genetics, Oncogene Proteins - metabolism, Promoter Regions, Genetic, Protein Structure, Tertiary, Proto-Oncogene Proteins c-myc - genetics, RNA, Small Interfering - administration & dosage, RNA, Small Interfering - genetics, Transcription Factors - antagonists & inhibitors, Transcription Factors - deficiency, Transcription Factors - genetics, Transcription Factors - metabolism, Transfection, Triazoles - pharmacology, Xenograft Model Antitumor Assays