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

• Published in: Nature chemical biology Vol. 9; no. 11; pp. 708 - 714
• Main Authors: Fallahi-Sichani, Mohammad, Honarnejad, Saman, Heiser, Laura M, Gray, Joe W, Sorger, Peter K
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2013; Nature Publishing Group
• Subjects: 631/154/1435/2163; 631/553; 631/92/436; 692/699/67; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer; Cell Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Cellular biology; Chemistry; Chemistry/Food Science; Chemotherapy; Dose-Response Relationship, Drug; Drugs; Female; Humans; Pharmacology; Structure-Activity Relationship
• ISSN: 1552-4450; 1552-4469; 1552-4469
• DOI: 10.1038/nchembio.1337

IC 50 values are widely used measures of compound potency. A multiparametric analysis of dose-response curves derived from a panel of cell lines treated with anticancer drugs reveals that there can be systematic variability in dose-response parameters across drug classes and cell types, effects that are not apparent by inspection of IC 50 values. Large-scale analysis of cellular response to anticancer drugs typically focuses on variation in potency (half-maximum inhibitory concentration, (IC 50 )), 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 ( E max ). We found that some of these parameters vary systematically with cell line and others with drug class. For cell-cycle inhibitors, E max 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 IC 50 .