Systematic identification of genomic markers of drug sensitivity in cancer cells
Garnett, Mathew J.; Edelman, Elena J.; Heidorn, Sonja J.; Greenman, Chris D.; Dastur, Anahita; Lau, King Wai; Greninger, Patricia; Thompson, I. Richard; Luo, Xi; Soares, Jorge; Liu, Qingsong; Iorio, Francesco; Surdez, Didier; Chen, Li; Milano, Randy J.; Bignell, Graham R.; Tam, Ah T.; Davies, Helen; Stevenson, Jesse A.; Barthorpe, Syd; Lutz, Stephen R.; Kogera, Fiona; Lawrence, Karl; McLaren-Douglas, Anne; Mitropoulos, Xeni; Mironenko, Tatiana; Thi, Helen; Richardson, Laura; Zhou, Wenjun; Jewitt, Frances; Zhang, Tinghu; Oâ Brien, Patrick; Boisvert, Jessica L.; Price, Stacey; Hur, Wooyoung; Yang, Wanjuan; Deng, Xianming; Butler, Adam; Choi, Hwan Geun; Chang, Jae Won; Baselga, Jose; Stamenkovic, Ivan; Engelman, Jeffrey A.; Sharma, Sreenath V.; Delattre, Olivier; Saez-Rodriguez, Julio; Gray, Nathanael S.; Settleman, Jeffrey; Futreal, P. Andrew; Haber, Daniel A.; Stratton, Michael R.; Ramaswamy, Sridhar; McDermott, Ultan; Benes, Cyril H.; Garnett, Mathew J.; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Edelman, Elena J.; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Heidorn, Sonja J.; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Greenman, Chris D.; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Department of Computing, University of East Anglia, Norwich NR4 7TJ, UK (C.D.G.); The Genome Analysis Centre, Norwich Research Park, Norwich NR4 7UH, UK (C.D.G.); Oncology Drug Discovery, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA (S.V.S.).; Dastur, Anahita; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Lau, King Wai; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Greninger, Patricia; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Thompson, I. Richard; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Luo, Xi; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Soares, Jorge; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Liu, Qingsong; Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, USA; Iorio, Francesco; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; EMBL-EBI, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK; Surdez, Didier; Laboratoire de génétique et biologie des cancers, Institut Curie, 75248 Paris, Cedex 05, France; Chen, Li; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Milano, Randy J.; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Bignell, Graham R.; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Tam, Ah T.; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Davies, Helen; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Stevenson, Jesse A.; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Barthorpe, Syd; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Lutz, Stephen R.; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Kogera, Fiona; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Lawrence, Karl; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; McLaren-Douglas, Anne; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Mitropoulos, Xeni; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Mironenko, Tatiana; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Thi, Helen; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Richardson, Laura; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Zhou, Wenjun; Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, USA; Jewitt, Frances; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Zhang, Tinghu; Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, USA; Oâ Brien, Patrick; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Boisvert, Jessica L.; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Price, Stacey; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Hur, Wooyoung; Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, USA; Yang, Wanjuan; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Deng, Xianming; Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, USA; Butler, Adam; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Choi, Hwan Geun; Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, USA; Chang, Jae Won; Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, USA; Baselga, Jose; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Stamenkovic, Ivan; Division of Experimental Pathology, Institute of Pathology, Centre Hospitalier Universitaire Vaudois (CHUV), 1005 Lausanne, Switzerland; Engelman, Jeffrey A.; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Sharma, Sreenath V.; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Department of Computing, University of East Anglia, Norwich NR4 7TJ, UK (C.D.G.); The Genome Analysis Centre, Norwich Research Park, Norwich NR4 7UH, UK (C.D.G.); Oncology Drug Discovery, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA (S.V.S.).; Delattre, Olivier; Laboratoire de génétique et biologie des cancers, Institut Curie, 75248 Paris, Cedex 05, France; Saez-Rodriguez, Julio; EMBL-EBI, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK; Gray, Nathanael S.; Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, USA; Settleman, Jeffrey; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Futreal, P. Andrew; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Haber, Daniel A.; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA; Stratton, Michael R.; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Ramaswamy, Sridhar; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; McDermott, Ultan; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Benes, Cyril H.; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA
Журнал:
Nature
Дата:
2012
Аннотация:
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 linesâ which represent much of the tissue-type and genetic diversity of human cancersâ 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 Ewingâ 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.
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