Nonlinear mixed-effects models for modeling in vitro drug response data to determine problematic cancer cell lines

Abstract

Abstract Cancer cell lines (CCLs) have been widely used to study of cancer. Recent studies have called into question the reliability of data collected on CCLs. Hence, we set out to determine CCLs that tend to be overly sensitive or resistant to a majority of drugs utilizing a nonlinear mixed-effects (NLME) modeling framework. Using drug response data collected in the Cancer Cell Line Encyclopedia (CCLE) and the Genomics of Drug Sensitivity in Cancer (GDSC), we determined the optimal functional form for each drug. Then, a NLME model was fit to the drug response data, with the estimated random effects used to determine sensitive or resistant CCLs. Out of the roughly 500 CCLs studies from the CCLE, we found 17 cell lines to be overly sensitive or resistant to the studied drugs. In the GDSC, we found 15 out of the 990 CCLs to be excessively sensitive or resistant. These results can inform researchers in the selection of CCLs to include in drug studies. Additionally, this study illustrates the need for assessing the dose-response functional form and the use of NLME models to achieve more stable estimates of drug response parameters.