CDK7 Inhibition Suppresses Super-Enhancer-Linked Oncogenic Transcription in MYCN-Driven Cancer
Author(s)
Chipumuro, Edmond; Marco, Eugenio; Christensen, Camilla L.; Zhang, Tinghu; Hatheway, Clark M.; Sharma, Bandana; Yeung, Caleb; Altabef, Abigail; Perez-Atayde, Antonio; Wong, Kwok-Kin; Yuan, Guo-Cheng; Gray, Nathanael S.; George, Rani E.; Kwiatkowski, Nick; Abraham, Brian Joseph; Young, Richard A.; ... Show more Show less
DownloadYoung_CDK7 inhibition.pdf (2.608Mb)
PUBLISHER_CC
Publisher with Creative Commons License
Creative Commons Attribution
Terms of use
Metadata
Show full item recordAbstract
The MYC oncoproteins are thought to stimulate tumor cell growth and proliferation through amplification of gene transcription, a mechanism that has thwarted most efforts to inhibit MYC function as potential cancer therapy. Using a covalent inhibitor of cyclin-dependent kinase 7 (CDK7) to disrupt the transcription of amplified MYCN in neuroblastoma cells, we demonstrate downregulation of the oncoprotein with consequent massive suppression of MYCN-driven global transcriptional amplification. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without the introduction of systemic toxicity. The striking treatment selectivity of MYCN-overexpressing cells correlated with preferential downregulation of super-enhancer-associated genes, including MYCN and other known oncogenic drivers in neuroblastoma. These results indicate that CDK7 inhibition, by selectively targeting the mechanisms that promote global transcriptional amplification in tumor cells, may be useful therapy for cancers that are driven by MYC family oncoproteins.
Date issued
2014-11Department
Broad Institute of MIT and Harvard; Massachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical ResearchJournal
Cell
Publisher
Elsevier
Citation
Chipumuro, Edmond; Marco, Eugenio; Christensen, Camilla L.; Kwiatkowski, Nicholas; Zhang, Tinghu; Hatheway, Clark M.; Abraham, Brian J.; et al. “CDK7 Inhibition Suppresses Super-Enhancer-Linked Oncogenic Transcription in MYCN-Driven Cancer.” Cell 159, no. 5 (November 2014): 1126–1139. © 2014 Elsevier Inc.
Version: Author's final manuscript
ISSN
0092-8674
1097-4172