Systematic identification of genomic markers of drug sensitivity in cancer cells

被引：1799

作者：

Garnett, Mathew J. ^{[1
]}

Edelman, Elena J. ^{[2
]}

Heidorn, Sonja J. ^{[1
]}

Greenman, Chris D. ^{[1
]}

Dastur, Anahita ^{[2
]}

Lau, King Wai ^{[1
]}

Greninger, Patricia ^{[2
]}

Thompson, I. Richard ^{[1
]}

Luo, Xi ^{[2
]}

Soares, Jorge ^{[1
]}

Liu, Qingsong ^{[3
,4
]}

Iorio, Francesco ^{[1
,5
]}

Surdez, Didier ^{[6
]}

Chen, Li ^{[2
]}

Milano, Randy J. ^{[2
]}

Bignell, Graham R. ^{[1
]}

Tam, Ah T.

Davies, Helen ^{[1
]}

Stevenson, Jesse A. ^{[2
]}

Barthorpe, Syd ^{[1
]}

Lutz, Stephen R. ^{[2
]}

Kogera, Fiona ^{[1
]}

Lawrence, Karl ^{[1
]}

McLaren-Douglas, Anne ^{[1
]}

Mitropoulos, Xeni ^{[2
]}

Mironenko, Tatiana ^{[1
]}

Thi, Helen ^{[2
]}

Richardson, Laura ^{[1
]}

Zhou, Wenjun ^{[3
,4
]}

Jewitt, Frances ^{[1
]}

Zhang, Tinghu ^{[3
,4
]}

O'Brien, Patrick ^{[1
]}

Boisvert, Jessica L. ^{[2
]}

Price, Stacey ^{[1
]}

Hur, Wooyoung ^{[3
,4
]}

Yang, Wanjuan ^{[1
]}

Deng, Xianming ^{[3
,4
]}

Butler, Adam ^{[1
]}

Choi, Hwan Geun ^{[3
,4
]}

Chang, JaeWon ^{[3
,4
]}

Baselga, Jose ^{[2
]}

Stamenkovic, Ivan ^{[7
]}

Engelman, Jeffrey A. ^{[2
]}

Sharma, Sreenath V. ^{[2
]}

Delattre, Olivier ^{[6
]}

Saez-Rodriguez, Julio ^{[5
]}

Gray, Nathanael S. ^{[3
,4
]}

Settleman, Jeffrey ^{[2
]}

Futreal, P. Andrew ^{[1
]}

Haber, Daniel A. ^{[2
,8
]}

机构：

[1] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England

[2] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Charlestown, MA 02129 USA

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

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

[5] EMBL EBI, Cambridge CB10 1SD, England

[6] Inst Curie, Lab Genet & Biol Canc, F-75248 Paris 05, France

[7] CHU Vaudois, Inst Pathol, Div Expt Pathol, CH-1005 Lausanne, Switzerland

[8] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

NATURE | 2012年 / 483卷 / 7391期

基金：

美国国家卫生研究院; 英国惠康基金; 美国国家科学基金会;

关键词：

MESENCHYMAL PROGENITOR CELLS; KINASE INHIBITOR; IN-VIVO; POLY(ADP-RIBOSE) POLYMERASE; EWINGS-SARCOMA; LUNG-CANCER; P53; PATHWAY; GROWTH; EXPRESSION; MELANOMA;

D O I：

10.1038/nature11005

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines-which represent much of the tissue-type and genetic diversity of human cancers-with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.

引用

页码：570 / U87

页数：8

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