Most analyses of cellular responses to anti-cancer drugs focus on variation in potency (e.g. GI50 or IC50) under the assumption that potency is the most important difference between effective and ineffective drugs or sensitive and resistant cells. We took a multi-parametric approach involving analysis of additional features such as maximum effect (Emax), the slope of the dose-response curve (Hill Slope; HS), and the area under the curve (AUC). We found that a subset of these parameters varies in a systematic manner with cell line and another subset with drug class. For cell cycle inhibitors, Emax generally correlates with cell proliferation rate but this is not always true: Emax ∼ 0 for S-phase specific drugs such as cisplatin, carboplatin and oxaliplatin across multiple cell lines. For drugs targeting the Akt/PI3K/mTOR pathway the slope of the dose-response curve is unusually shallow (HS << 1). 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 IC50.
Citation Format: Mohammad Fallahi-Sichani, Saman Honarnejad, Laura M. Heiser, Joe W. Gray, Peter K. Sorger. Metrics other than potency reveal systematic variation in responses to cancer drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5502. doi:10.1158/1538-7445.AM2014-5502