Abstract
Large-scale analysis of cellular response to anticancer drugs typically focuses on variation in potency (half-maximum inhibitory concentration, (IC50)), assuming that it is the most important difference between effective and ineffective drugs or sensitive and resistant cells. We took a multiparametric approach involving analysis of the slope of the dose-response curve, the area under the curve and the maximum effect (Emax). We found that some of these parameters vary systematically with cell line and others with drug class. For cell-cycle inhibitors, Emax often but not always correlated with cell proliferation rate. For drugs targeting the Akt/PI3K/mTOR pathway, dose-response curves were unusually shallow. Classical pharmacology has no ready explanation for this phenomenon, but single-cell analysis showed that it correlated with significant and heritable cell-to-cell variability in the extent of target inhibition. We conclude that parameters other than potency should be considered in the comparative analysis of drug response, particularly at clinically relevant concentrations near and above the IC50.
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Acknowledgements
We thank W. Chen, G. Berriz, M. Niepel, M. Hafner, D. Flusberg, T. Mitchison, D. Marks and C. Shamu for help. This work was supported by the US National Institutes of Health–Library of Integrated Network-Based Cellular Signatures Program grant HG006097 to P.K.S. and by Stand Up to Cancer grant AACR-SU2C-DT0409 to P.K.S. and J.W.G. M.F.-S. is supported by a Merck Fellowship of the Life Sciences Research Foundation.
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M.F.-S. designed and performed the experiments, analyzed the experimental data, performed statistical analyses and wrote the manuscript. S.H. designed and performed the experiments and wrote the manuscript. L.M.H. designed and performed the experiments and wrote the manuscript. J.W.G. designed the experiments and wrote the manuscript. P.K.S. designed the experiments and wrote the manuscript.
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Fallahi-Sichani, M., Honarnejad, S., Heiser, L. et al. Metrics other than potency reveal systematic variation in responses to cancer drugs. Nat Chem Biol 9, 708–714 (2013). https://doi.org/10.1038/nchembio.1337
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DOI: https://doi.org/10.1038/nchembio.1337