CDK7 Inhibition Suppresses Super-Enhancer-Linked Oncogenic Transcription in MYCN-Driven Cancer

被引：561

作者：

Chipumuro, Edmond ^{[1
,2
,3
]}

Marco, Eugenio ^{[4
,5
]}

Christensen, Camilla L. ^{[6
]}

Kwiatkowski, Nicholas ^{[7
,8
]}

Zhang, Tinghu ^{[9
,10
]}

Hatheway, Clark M. ^{[1
,2
]}

Abraham, Brian J. ^{[7
,8
]}

Sharma, Bandana ^{[1
,2
]}

Yeung, Caleb ^{[1
,2
,3
]}

Altabef, Abigail ^{[6
]}

Perez-Atayde, Antonio ^{[11
]}

Wong, Kwok-Kin ^{[6
]}

Yuan, Guo-Cheng ^{[4
,5
]}

Gray, Nathanael S. ^{[9
,10
]}

Young, Richard A. ^{[7
,8
]}

George, Rani E. ^{[1
,2
,3
]}

机构：

[1] Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02215 USA

[2] Boston Childrens Hosp, Boston, MA 02215 USA

[3] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA

[4] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA

[5] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA

[6] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[7] MIT, Whitehead Inst Biomed Res, Cambridge, MA 02139 USA

[8] MIT, Dept Biol, Cambridge, MA 02139 USA

[9] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[10] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[11] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA

来源：

CELL | 2014年 / 159卷 / 05期

关键词：

BET BROMODOMAIN INHIBITION; RNA-POLYMERASE-II; N-MYC; C-MYC; ACTIVATING KINASE; THERAPEUTIC TARGETS; CELLULAR GROWTH; GENE-EXPRESSION; LYMPHOMA-CELLS; NEUROBLASTOMA;

D O I：

10.1016/j.cell.2014.10.024

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：1126 / 1139

页数：14

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