Abstract
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 (bromodomain and extra-terminal domain) 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 demonstrated downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription, and a BET Bromodomain inhibitor was found to displace BRD4 from the MYCN promoter region in neuroblastoma cell lines. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knock-down phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in three in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. Citation Format: Alexandre Puissant, Stacey M. Frumm, Gabriela Alexe, Christopher F. Bassil, Jun Qi, Yvan H. Chanthery, Erin A. Nekritz, Rhamy Zeid, W. Clay Gustafson, Patricia Greninger, Matthew J. Garnett, Ultan McDermott, Cyril H. Benes, Andrew L. Kung, William A. Weiss, James E. Bradner, Kimberly Stegmaier. Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4622. doi:10.1158/1538-7445.AM2013-4622
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
