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CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer.

Abstract：

: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.

journal_name

Cell

journal_title

Cell

authors

Chipumuro E,Marco E,Christensen CL,Kwiatkowski N,Zhang T,Hatheway CM,Abraham BJ,Sharma B,Yeung C,Altabef A,Perez-Atayde A,Wong KK,Yuan GC,Gray NS,Young RA,George RE

doi

10.1016/j.cell.2014.10.024

subject

Has Abstract

pub_date

2014-11-20 00:00:00

pages

1126-1139

issue

5

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(14)01312-9

journal_volume

159

pub_type

杂志文章

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