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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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.
Integrated supplementary information
Genomic correlates of PRISM sensitivity profiles
About this article
Nature Methods (2016)