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Linking pathway gene expressions to the growth inhibition response from the National Cancer Institute's anticancer screen and drug mechanism of action

Abstract

Novel strategies are proposed to quantitatively analyze and relate biological pathways to drug responses using gene expression and small-molecule growth inhibition data (GI50) derived from the National Cancer Institute's 60 cancer cells (NCI60). We have annotated groups of drug GI50 responses with pathways defined by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and BioCarta, and functional categories defined by Gene Ontology (GO), through correlations between pathway gene expression patterns and drug GI50 profiles. Drug–gene-pathway relationships may then be utilized to find drug targets or target-specific drugs. Significantly correlated pathways and the gene products involved represent interesting targets for further exploration, whereas drugs that are significantly correlated with only certain pathways are more likely to be target specific. Separate pathway clustering finds that pathways engaged in the same biological process tend to have similar drug correlation patterns. The biological and statistical significances of our method are established by comparison to known small-molecule inhibitor–gene target relationships reported in the literature and by standard randomization procedures. The results of our pathway, gene expression and drug-induced growth inhibition associations, can serve as a basis for proposing testable hypotheses about potential anticancer drugs, their targets, and mechanisms of action.

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Acknowledgements

We thank the members of the STB staff, especially Drs Robert Shoemaker and Susan Mertins, for valuable contributions during the preparation of this manuscript. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-12400. The content of this publication does not necessarily reflect the view or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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Correspondence to D G Covell.

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Our reference to ‘drug’ in this manuscript is not a clinical ‘drug’ per se, but generally a small-molecule compound that has been screened in the NCI60 for anticancer acticity.

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None declared.

Supplementary Information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website (http://www.nature.com/tpj).

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Huang, R., Wallqvist, A., Thanki, N. et al. Linking pathway gene expressions to the growth inhibition response from the National Cancer Institute's anticancer screen and drug mechanism of action. Pharmacogenomics J 5, 381–399 (2005). https://doi.org/10.1038/sj.tpj.6500331

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