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bioRxiv · 10.1101/700153

A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity

Santos, S. M.·Icyuz, M.·Pound, I.·William, D.·Guo, J.·McKinney, B. A.·Niederweis, M.·Rodgers, J. W.·Hartman, J. L.
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Abstract

Knowledge about synthetic lethality can be applied to enhance the efficacy of anti-cancer therapies in individual patients harboring genetic alterations in their cancer that specifically render it vulnerable. We investigated the potential for high-resolution phenomic analysis in yeast to predict such genetic vulnerabilities by systematic, comprehensive, and quantitative assessment of drug-gene interaction for gemcitabine and cytarabine, substrates of deoxycytidine kinase that have similar molecular structures yet distinct anti-tumor efficacy. Human deoxycytidine kinase (dCK) was conditionally expressed in the S. cerevisiae genomic library of knockout and knockdown (YKO/KD) strains, to globally and quantitatively characterize differential drug-gene interaction for gemcitabine and cytarabine. Pathway enrichment analysis revealed that autophagy, histone modification, chromatin remodeling, and apoptosis-related processes influence gemcitabine specifically, while drug-gene interaction specific to cytarabine was less enriched in Gene Ontology. Processes having influence over both drugs were DNA repair and integrity checkpoints and vesicle transport and fusion. Non-GO-enriched genes were also informative. Yeast phenomic and cancer cell line pharmacogenomics data were integrated to identify yeast-human homologs with correlated differential gene expression and drug-efficacy, thus providing a unique resource to predict whether differential gene expression observed in cancer genetic profiles are causal in tumor-specific responses to cytotoxic agents.

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Santos, S. M., Icyuz, M., Pound, I., William, D., Guo, J., McKinney, B. A., Niederweis, M., Rodgers, J. W., Hartman, J. L.. 2019-07-22. A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity. https://doi.org/10.1101/700153

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