Systematic identification of genomic markers of drug sensitivity in cancer cells

Mathew J. Garnett, Elena J. Edelman, Sonja J. Heidorn, Chris D. Greenman, Anahita Dastur, King Wai Lau, Patricia Greninger, I. Richard Thompson, Xi Luo, Jorge Soares, Qingsong Liu, Francesco Iorio, Didier Surdez, Li Chen, Randy J. Milano, Graham R. Bignell, Ah T. Tam, Helen Davies, Jesse A. Stevenson, Syd Barthorpe, Stephen R. Lutz, Fiona Kogera, Karl Lawrence, Anne McLaren-Douglas, Xeni Mitropoulos, Tatiana Mironenko, Helen Thi, Laura Richardson, Wenjun Zhou, Frances Jewitt, Tinghu Zhang, Patrick O’Brien, Jessica L. Boisvert, Stacey Price, Wooyoung Hur, Wanjuan Yang, Xianming Deng, Adam Butler, Hwan Geun Choi, Jae Won Chang, Jose Baselga, Ivan Stamenkovic, Jeffrey A. Engelman, Sreenath V. Sharma, Olivier Delattre, Julio Saez-Rodriguez, Nathanael S. Gray, Jeffrey Settleman, P. Andrew Futreal, Daniel A. Haber, Michael R. Stratton, Sridhar Ramaswamy, Ultan McDermott () and Cyril H. Benes ()
Additional contact information
Mathew J. Garnett: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Elena J. Edelman: Massachusetts General Hospital Cancer Center, Harvard Medical School
Sonja J. Heidorn: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Chris D. Greenman: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Anahita Dastur: Massachusetts General Hospital Cancer Center, Harvard Medical School
King Wai Lau: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Patricia Greninger: Massachusetts General Hospital Cancer Center, Harvard Medical School
I. Richard Thompson: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Xi Luo: Massachusetts General Hospital Cancer Center, Harvard Medical School
Jorge Soares: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Qingsong Liu: Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA
Francesco Iorio: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Didier Surdez: Laboratoire de génétique et biologie des cancers, Institut Curie, 75248 Paris, Cedex 05, France
Li Chen: Massachusetts General Hospital Cancer Center, Harvard Medical School
Randy J. Milano: Massachusetts General Hospital Cancer Center, Harvard Medical School
Graham R. Bignell: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Ah T. Tam: Massachusetts General Hospital Cancer Center, Harvard Medical School
Helen Davies: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Jesse A. Stevenson: Massachusetts General Hospital Cancer Center, Harvard Medical School
Syd Barthorpe: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Stephen R. Lutz: Massachusetts General Hospital Cancer Center, Harvard Medical School
Fiona Kogera: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Karl Lawrence: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Anne McLaren-Douglas: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Xeni Mitropoulos: Massachusetts General Hospital Cancer Center, Harvard Medical School
Tatiana Mironenko: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Helen Thi: Massachusetts General Hospital Cancer Center, Harvard Medical School
Laura Richardson: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Wenjun Zhou: Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA
Frances Jewitt: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Tinghu Zhang: Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA
Patrick O’Brien: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Jessica L. Boisvert: Massachusetts General Hospital Cancer Center, Harvard Medical School
Stacey Price: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Wooyoung Hur: Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA
Wanjuan Yang: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Xianming Deng: Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA
Adam Butler: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Hwan Geun Choi: Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA
Jae Won Chang: Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA
Jose Baselga: Massachusetts General Hospital Cancer Center, Harvard Medical School
Ivan Stamenkovic: Institute of Pathology, Centre Hospitalier Universitaire Vaudois (CHUV), 1005 Lausanne, Switzerland
Jeffrey A. Engelman: Massachusetts General Hospital Cancer Center, Harvard Medical School
Sreenath V. Sharma: Massachusetts General Hospital Cancer Center, Harvard Medical School
Olivier Delattre: Laboratoire de génétique et biologie des cancers, Institut Curie, 75248 Paris, Cedex 05, France
Julio Saez-Rodriguez: EMBL-EBI, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK
Nathanael S. Gray: Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA
Jeffrey Settleman: Massachusetts General Hospital Cancer Center, Harvard Medical School
P. Andrew Futreal: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Daniel A. Haber: Massachusetts General Hospital Cancer Center, Harvard Medical School
Michael R. Stratton: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Sridhar Ramaswamy: Massachusetts General Hospital Cancer Center, Harvard Medical School
Ultan McDermott: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Cyril H. Benes: Massachusetts General Hospital Cancer Center, Harvard Medical School

Nature, 2012, vol. 483, issue 7391, 570-575

Abstract: Abstract 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.

Date: 2012
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DOI: 10.1038/nature11005

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