Targeting MYCN in neuroblastoma by BET bromodomain inhibition.
Cancer Discov
; 3(3): 308-23, 2013 Mar.
Article
en En
| MEDLINE
| ID: mdl-23430699
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.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Factores de Transcripción
/
Proteínas Nucleares
/
Proteínas Oncogénicas
/
Neuroblastoma
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Cancer Discov
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos