Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor

被引：406

作者：

Christensen, Camilla L. ^{[1
]}

Kwiatkowski, Nicholas ^{[2
]}

Abraham, Brian J. ^{[2
]}

Carretero, Julian ^{[3
]}

Al-Shahrour, Fatima ^{[4
]}

Zhang, Tinghu ^{[5
]}

Chipumuro, Edmond ^{[6
,7
]}

Herter-Sprie, Grit S. ^{[1
]}

Akbay, Esra A. ^{[1
]}

Altabef, Abigail ^{[1
]}

Zhang, Jianming ^{[5
]}

Shimamura, Takeshi ^{[8
]}

Capelletti, Marzia ^{[1
]}

Reibel, Jakob B. ^{[1
]}

Cavanaugh, Jillian D. ^{[1
]}

Gao, Peng ^{[1
]}

Liu, Yan ^{[1
]}

Michaelsen, Signe R. ^{[9
]}

Poulsen, Hans S. ^{[9
]}

Aref, Amir R. ^{[1
]}

Barbie, David A. ^{[1
]}

Bradner, James E. ^{[1
]}

George, Rani E. ^{[6
,7
]}

Gray, Nathanael S. ^{[5
,11
]}

Young, Richard A. ^{[2
,10
]}

Won, Kwok-Kin ^{[1
,11
]}

机构：

[1] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA

[2] MIT, Whitehead Inst Biomed Res, 77 Massachusetts Ave, Cambridge, MA 02142 USA

[3] Univ Valencia, Fac Farm, Dept Fisiol, E-46010 Valencia, Spain

[4] Spanish Natl Canc Res Ctr, Translat Bioinformat Unit, Clin Res Programme, Madrid 28029, Spain

[5] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[6] Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA

[7] Childrens Hosp, Boston, MA 02115 USA

[8] Loyola Univ Chicago, Dept Mol Pharmacol & Therapeut, Oncol Res Inst, Stritch Sch Med, Maywood, IL 60153 USA

[9] Univ Copenhagen Hosp, Dept Radiat Biol, Finsen Ctr, DK-2100 Copenhagen, Denmark

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

[11] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA

来源：

CANCER CELL | 2014年 / 26卷 / 06期

基金：

美国国家卫生研究院;

关键词：

GENE-EXPRESSION; NEUROENDOCRINE DIFFERENTIATION; SELECTIVE-INHIBITION; SUPER-ENHANCERS; TUMOR-CELLS; AMPLIFICATION; GENOME; SIGNATURES; CARCINOMA; ONCOGENE;

D O I：

10.1016/j.ccell.2014.10.019

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Small cell lung cancer (SCLC) is an aggressive disease with high mortality, and the identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library, we observe that SCLC is sensitive to transcription-targeting drugs, in particular to THZ1, a recently identified covalent inhibitor of cyclin-dependent kinase 7. We find that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a prototype drug for tailored SCLC therapy.

引用

页码：909 / 922

页数：14

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