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Systematic identification of genomic markers of drug sensitivity in cancer cells

Author

Listed:
  • 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
    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.).)

  • 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
    Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • Francesco Iorio

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
    EMBL-EBI, Wellcome Trust Genome Campus, Cambridge CB10 1SD, 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
    Harvard Medical School, 250 Longwood Avenue, 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
    Harvard Medical School, 250 Longwood Avenue, 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
    Harvard Medical School, 250 Longwood Avenue, 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
    Harvard Medical School, 250 Longwood Avenue, 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
    Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • Jae Won Chang

    (Dana Farber Cancer Institute, 44 Binney Street, Boston Massachusetts 02115, USA
    Harvard Medical School, 250 Longwood Avenue, 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
    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.).)

  • 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
    Harvard Medical School, 250 Longwood Avenue, 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
    Howard Hughes Medical Institute)

  • 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)

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.

Suggested Citation

  • 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 & Francesc, 2012. "Systematic identification of genomic markers of drug sensitivity in cancer cells," Nature, Nature, vol. 483(7391), pages 570-575, March.
    • Handle: RePEc:nat:nature:v:483:y:2012:i:7391:d:10.1038_nature11005
    DOI: 10.1038/nature11005
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    Cited by:

    1. G. Gambardella & G. Viscido & B. Tumaini & A. Isacchi & R. Bosotti & D. di Bernardo, 2022. "A single-cell analysis of breast cancer cell lines to study tumour heterogeneity and drug response," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Jurica Levatić & Marina Salvadores & Francisco Fuster-Tormo & Fran Supek, 2022. "Mutational signatures are markers of drug sensitivity of cancer cells," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Shi, Chengchun & Xu, Tianlin & Bergsma, Wicher & Li, Lexin, 2021. "Double generative adversarial networks for conditional independence testing," LSE Research Online Documents on Economics 112550, London School of Economics and Political Science, LSE Library.
    4. Yang Sun & Lu Hu & Zhipeng Tao & Gopala K. Jarugumilli & Hannah Erb & Alka Singh & Qi Li & Jennifer L. Cotton & Patricia Greninger & Regina K. Egan & Y. Tony Ip & Cyril H. Benes & Jianwei Che & Junhao, 2022. "Pharmacological blockade of TEAD–YAP reveals its therapeutic limitation in cancer cells," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    5. Seonghun Kim & Seockhun Bae & Yinhua Piao & Kyuri Jo, 2021. "Graph Convolutional Network for Drug Response Prediction Using Gene Expression Data," Mathematics, MDPI, vol. 9(7), pages 1-17, April.
    6. Han Jin & Cheng Zhang & Martin Zwahlen & Kalle Feilitzen & Max Karlsson & Mengnan Shi & Meng Yuan & Xiya Song & Xiangyu Li & Hong Yang & Hasan Turkez & Linn Fagerberg & Mathias Uhlén & Adil Mardinoglu, 2023. "Systematic transcriptional analysis of human cell lines for gene expression landscape and tumor representation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    7. Ding, Hui & Zhang, Jian & Zhang, Riquan, 2022. "Nonparametric variable screening for multivariate additive models," Journal of Multivariate Analysis, Elsevier, vol. 192(C).
    8. Hanwen Xu & Addie Woicik & Hoifung Poon & Russ B. Altman & Sheng Wang, 2023. "Multilingual translation for zero-shot biomedical classification using BioTranslator," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    9. Nishanth Ulhas Nair & Patricia Greninger & Xiaohu Zhang & Adam A. Friedman & Arnaud Amzallag & Eliane Cortez & Avinash Das Sahu & Joo Sang Lee & Anahita Dastur & Regina K. Egan & Ellen Murchie & Miche, 2023. "A landscape of response to drug combinations in non-small cell lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    10. Wesley Tansey & Yixin Wang & Raul Rabadan & David Blei, 2020. "Double Empirical Bayes Testing," International Statistical Review, International Statistical Institute, vol. 88(S1), pages 91-113, December.
    11. L. Mathur & B. Szalai & N. H. Du & R. Utharala & M. Ballinger & J. J. M. Landry & M. Ryckelynck & V. Benes & J. Saez-Rodriguez & C. A. Merten, 2022. "Combi-seq for multiplexed transcriptome-based profiling of drug combinations using deterministic barcoding in single-cell droplets," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    12. Min Pan & William C. Wright & Richard H. Chapple & Asif Zubair & Manbir Sandhu & Jake E. Batchelder & Brandt C. Huddle & Jonathan Low & Kaley B. Blankenship & Yingzhe Wang & Brittney Gordon & Payton A, 2021. "The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    13. Hyeong-Min Lee & William C. Wright & Min Pan & Jonathan Low & Duane Currier & Jie Fang & Shivendra Singh & Stephanie Nance & Ian Delahunty & Yuna Kim & Richard H. Chapple & Yinwen Zhang & Xueying Liu , 2023. "A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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