Abstract

Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control1,2,3,4. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo.

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Acknowledgements

We thank S. Kim, G. Bonamy, J. (J.) Che, J. Thibault, T. Huynh, I. Engels and A. Shipway at Novartis for sharing data before publication; A. Christie and T. Davis for technical assistance in animal studies; C. Hartland, S. Donovan, E. Rubin and E. Winchester for technical assistance in compound assays; J. Bittker, J. McGrath and G. Wendel for assistance in compound management; S. Le Quement and J. Duvall for assistance in compound synthesis; J. Gale for technical assistance in enzyme kinetic assays; S. Howell for assistance in curation of computational data sets; A. Koehler, S. Dandapani, B. Muñoz, C. Scherer, D. Gray, D. Bachovchin, S. Santaguida and J. Elkins for expert scientific guidance; J. Barretina, N. Stransky, S. Nijman, B. Julian, W. Read-Button, J. Davis and D. Peck for technical advice; and members of the Golub laboratory for critical review of the manuscript. This work was supported in part by the US National Institutes of Health (NIH) Genomics Based Drug Discovery consortium grants RL1-CA133834, RL1-GM084437 and UL1DE019585 (administratively linked to NIH grant RL1-HG004671), US National Cancer Institute Integrative Cancer Biology Program grant U54CA112962, the Howard Hughes Medical Institute, the Claudia Adams Barr Program in Cancer Research Innovative Basic Science Research Program Grant, the American Society of Clinical Oncology Conquer Cancer Foundation Young Investigator Award and the Prostate Cancer Foundation.

Author information

Author notes

    • Griselda Metta Yvone
    • , Kenneth N Ross
    • , Michelle A Palmer
    • , Michael A Foley
    •  & Andrew L Kung

    Present addresses: University of California, Los Angeles, Los Angeles, California, USA (G.M.Y.), Massachusetts General Hospital, Boston, Massachusetts, USA (K.N.R.), ImmunoGen, Waltham, Massachusetts, USA (M.A.P.), Tri-Institutional Therapeutics Discovery Institute, New York, New York, USA (M.A.F.) and Columbia University Medical Center, New York, New York, USA (A.L.K.).

Affiliations

  1. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Channing Yu
    • , Aristotle M Mannan
    • , Griselda Metta Yvone
    • , Kenneth N Ross
    • , Yan-Ling Zhang
    • , Melissa A Marton
    • , Bradley R Taylor
    • , Andrew Crenshaw
    • , Joshua Z Gould
    • , Pablo Tamayo
    • , Barbara A Weir
    • , Aviad Tsherniak
    • , Bang Wong
    • , Levi A Garraway
    • , Alykhan F Shamji
    • , Michelle A Palmer
    • , Michael A Foley
    • , Wendy Winckler
    • , Stuart L Schreiber
    •  & Todd R Golub
  2. Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Channing Yu
    • , Levi A Garraway
    • , Andrew L Kung
    •  & Todd R Golub
  3. Harvard Medical School, Boston, Massachusetts, USA.

    • Channing Yu
    • , Levi A Garraway
    • , Andrew L Kung
    •  & Todd R Golub
  4. Harvard University, Cambridge, Massachusetts, USA.

    • Stuart L Schreiber
  5. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Stuart L Schreiber
    •  & Todd R Golub

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Contributions

C.Y. and T.R.G. designed the PRISM method and wrote the manuscript. C.Y., G.M.Y. and A.M.M. performed the experiments in the study. L.A.G. provided cell lines and drug response validation data from the Cancer Cell Line Encyclopedia Project. B.A.W. performed cell line genotype verification analyses. K.N.R. and P.T. contributed to statistical analyses of PRISM validation data. J.Z.G. and C.Y. created data processing and data visualization tools. M.A.P., W.W., A.C., M.A.M., B.R.T., G.M.Y., A.M.M. and C.Y. performed the large-scale PRISM screen. A.T. and C.Y. performed genomic correlation analyses in the large-scale PRISM screen. A.F.S. and S.L.S. contributed to compound creation and curation and design of experiments with BRD-7880. Y.-L.Z. performed kinetic kinase inhibition experiments with BRD-7880. A.L.K., C.Y. and T.R.G. contributed to design and execution of in vivo PRISM experiments. B.W. contributed to data visualization tools and to manuscript figures. All authors discussed the results and commented on the manuscript.

Competing interests

C.Y. and T.R.G. are inventors in patent application PCT/US2013/031312.

Corresponding author

Correspondence to Todd R Golub.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–2 and Supplementary Methods, Supplementary Table 8 and 9

  2. 2.

    Suppl_Figure_8b_GOLUB.pdf

    Hierarchical clustering of bioactive compounds by activity against 102 barcoded cell lines.

Excel files

  1. 1.

    Supplementary Table 1

    PRISM AUC (Area Under the Curve) measurements of cell viability

  2. 2.

    Supplementary Table 2

    PRISM cell viability of 8,000 Diversity-Oriented Synthesis (DOS) compounds at single dose across 102 cell lines

  3. 3.

    Supplementary Table 3

    PRISM cell viability across 8 or more doses of 400 tool compounds or oncology drugs with known mechanism-of-action and BRD-7880

  4. 4.

    Supplementary Table 4

    SNP fingerprinting of 102 cell lines

  5. 5.

    Supplementary Table 6

    PRISM cell viability across 8 doses of 199 DOS compounds

  6. 6.

    Supplementary Table 7

    PRISM cell viability across 8 doses of tozasertib and BRD-7880

Zip files

  1. 1.

    Supplementary Table 5

    Genomic correlates of PRISM sensitivity profiles

About this article

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DOI

https://doi.org/10.1038/nbt.3460

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