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.

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Acknowledgements

We thank P. Lo Grasso of the Scripps Research Institute for providing the inhibitor JNK9L. This work was supported by a grant from the Wellcome Trust (086357; M.R.S., P.A.F., J.S., D.A.H.) and by grants from the National Institutes of Health (P41GM079575-02 to N.S.G. and 1U54HG006097-01 to N.S.G. and D.A.H.). S.R. is supported by a Physician-Scientist Early Career Award from the Howard Hughes Medical Institute. U.M. is supported by a Cancer Research UK Clinician Scientist Fellowship.

Author information

Author notes

    • Mathew J. Garnett
    • , Elena J. Edelman
    •  & Sonja J. Heidorn

    These authors contributed equally to this work.

    • Chris D. Greenman
    •  & Sreenath V. Sharma

    Present addresses: 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.).

Affiliations

  1. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK

    • Mathew J. Garnett
    • , Sonja J. Heidorn
    • , Chris D. Greenman
    • , King Wai Lau
    • , I. Richard Thompson
    • , Jorge Soares
    • , Francesco Iorio
    • , Graham R. Bignell
    • , Helen Davies
    • , Syd Barthorpe
    • , Fiona Kogera
    • , Karl Lawrence
    • , Anne McLaren-Douglas
    • , Tatiana Mironenko
    • , Laura Richardson
    • , Frances Jewitt
    • , Patrick O’Brien
    • , Stacey Price
    • , Wanjuan Yang
    • , Adam Butler
    • , P. Andrew Futreal
    • , Michael R. Stratton
    •  & Ultan McDermott
  2. Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA

    • Elena J. Edelman
    • , Anahita Dastur
    • , Patricia Greninger
    • , Xi Luo
    • , Li Chen
    • , Randy J. Milano
    • , Ah T. Tam
    • , Jesse A. Stevenson
    • , Stephen R. Lutz
    • , Xeni Mitropoulos
    • , Helen Thi
    • , Jessica L. Boisvert
    • , Jose Baselga
    • , Jeffrey A. Engelman
    • , Sreenath V. Sharma
    • , Jeffrey Settleman
    • , Daniel A. Haber
    • , Sridhar Ramaswamy
    •  & Cyril H. Benes
  3. Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA

    • Qingsong Liu
    • , Wenjun Zhou
    • , Tinghu Zhang
    • , Wooyoung Hur
    • , Xianming Deng
    • , Hwan Geun Choi
    • , Jae Won Chang
    •  & Nathanael S. Gray
  4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, USA

    • Qingsong Liu
    • , Wenjun Zhou
    • , Tinghu Zhang
    • , Wooyoung Hur
    • , Xianming Deng
    • , Hwan Geun Choi
    • , Jae Won Chang
    •  & Nathanael S. Gray
  5. EMBL-EBI, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK

    • Francesco Iorio
    •  & Julio Saez-Rodriguez
  6. Laboratoire de génétique et biologie des cancers, Institut Curie, 75248 Paris, Cedex 05, France

    • Didier Surdez
    •  & Olivier Delattre
  7. Division of Experimental Pathology, Institute of Pathology, Centre Hospitalier Universitaire Vaudois (CHUV), 1005 Lausanne, Switzerland

    • Ivan Stamenkovic
  8. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA

    • Daniel A. Haber

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Contributions

M.J.G., C.H.B., U.M. and S.V.S. supervised data collection. M.J.G., C.H.B., U.M. and S.R. supervised data analysis. C.D.G. and K.W.L. conceived and wrote the curve-fitting algorithm and performed the MANOVA; E.J.E. and S.R. performed elastic net analysis and analysed the data. P.G., I.R.T. and J.So. developed and managed screening databases with assistance from A.B. and W.Y.; S.J.H. performed most of the Ewing’s sarcoma related studies with contributions from D.S., A.D., X.L., F.K. and L.C., with I.S. and O.D. providing critical reagents; R.J.M., A.T.T., J.A.S., S.B., S.R.L., K.L., A.M.-D., J.L.B., X.M., T.M., H.T., L.R., F.J. and P.O’B. performed cell line screening experiments. S.P. performed MCL1 siRNA experiments. Q.L.,W.Z., T.Z., W.H., X.D., H.G.C. and J.W.C. synthesized screening compounds, and N.S.G. provided guidance on their selection and use; F.I. and J.S.-R. performed compound activity clustering; G.R.B. and H.D. performed cell line genotyping and genetic analysis; J.A.E. and J.B. provided guidance regarding clinical relevance of the work; M.J.G. and C.H.B. wrote the manuscript with major contributions from S.R., S.J.H. and U.M.; M.R.S., D.A.H., J.Se. and P.A.F. conceived the study, analysed the data and edited the manuscript.

Competing interests

J.Se. is currently an employee of Genentech and is a shareholder of Roche.

Corresponding authors

Correspondence to Ultan McDermott or Cyril H. Benes.

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    This file contains Supplementary Data 1-11. This file was replaced on 13 April 2012, as the original file posted on line had corrupted, and some of the data was missing from tables 1 and 11.

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https://doi.org/10.1038/nature11005

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