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Metrics other than potency reveal systematic variation in responses to cancer drugs

Nature Chemical Biology volume 9, pages 708–714 (2013)Cite this article

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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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Figure 1: Diversity of anticancer compounds with respect to variation in dose-response parameters across a panel of breast cell lines.
Figure 2: Selected examples of dose-response curves representing different types of variation in dose-response relationships.
Figure 3: Different dose-response parameters do not always correlate with each other.
Figure 4: Association of dose-response parameters with cell type, drug type and drug class.
Figure 5: High cell-to-cell variability is associated with shallow dose-response and suboptimal maximum effect for pharmacological inhibition of mTOR.
Figure 6: Different dose-response parameters capture cell line to cell line variation at different dose regimes.

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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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Authors and Affiliations

  1. Department of Systems Biology, Harvard Medical School Library of Integrated Network-based Cellular Signatures Center, Harvard Medical School, Boston, Massachusetts, USA

    Mohammad Fallahi-Sichani, Saman Honarnejad & Peter K Sorger

  2. Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, USA

    Laura M Heiser & Joe W Gray

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  1. Mohammad Fallahi-Sichani
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Contributions

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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Correspondence to Peter K Sorger.

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The authors declare no competing financial interests.

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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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