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

Abstract

Large-scale analysis of cellular response to anti-cancer drugs typically focuses on variation in potency (IC50) assuming that it is the most important difference between effective/ineffective drugs or sensitive/resistant cells. We took a multi-parametric approach involving analysis of the slope of the dose-response curve (HS), the area under the curve (AUC) 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 IC50.

A Functional Cancer Genomics Screen Identifies a Druggable Synthetic Lethal Interaction between MSH3 and PRKDC

“…1 ). As reported recently ( 38 ), potency and selectivity of several compounds are underestimated, if analysis is restricted to their half maximal growth-inhibitory concentrations (GI 50 ). Hence, we amended our interpretation of the cell line screen by Hill coeffi cients and nearest-neighbor distances (Supplementary Fig.…”

Cellular uptake and anticancer activity of carboxylated gallium corroles

“…2). Although correlation of E max with cell proliferation rate has often been shown for cell cycle inhibitors (48), the fraction kill theory does not always apply. For instance, Oxamflatin and NSC663284, which arrest cells at both G 1 and G 2 /M, exhibit high efficacy (E max = 0) in all 64 breast cancer cell lines tested with varying cell proliferation rates.…”

“…2). In general, E max is defined between 1 at low doses and 0 at high doses, which corresponds to 100% cytotoxicity (48). With the exception of 1 in MDA-MB-231 cells (E max = 0.25), the maximum cytotoxic effect for all compounds tested was ≤0.02, indicating high efficacy (Fig.…”

“…The lower efficacy of 1 in MDA-MB-231 cells may be explained in part by the "fraction kill" theory, which proposes that inhibitors of cell cycle progression, such as paclitaxel and docetaxel, kill only the subset of cells that pass through S or M phases in the presence of the drug (49,50). Therefore, cells with substantially longer doubling times, and thus smaller mitotic and S-phase fractions, would have higher values for E max (48). Because gallium corroles were previously shown to arrest cells at the late M phase (41) (Fig.…”

“…Although the IC 50 value is typically the principal metric for the effectiveness of a potential drug, other parameters involving the slope of the dose-response curve (Hill slope, ‫)|‪γ‬|‬ and the maximum effect (E max ), which represent the compound's range of useful concentrations and efficacy, respectively, also should be considered in evaluating drug response (47,48). For example, a drug with low efficacy may only kill 20% of cells even at the highest doses (E max = 0.8), or a drug could have a shallow doseresponse curve ‫|‪γ‬|(‬ < 1), meaning that the therapeutic benefit or cytotoxic effect may not increase substantially as the maximum tolerated dose is approached.…”