Combining drugs can enhance their clinical effectiveness, but the vast number of possible combinations and the variability between tumors make it challenging to identify effective pairings. Furthermore, existing methods often overlook clinically significant activity. In this study, we screened one of the largest cell line panels (N = 757) using 51 clinically relevant drug combinations, evaluating responses at both the individual cell line and tissue population levels.
We established three response categories to model cellular effects beyond monotherapy: synergy, Bliss additivity, and independent drug action (IDA). Synergy is rare, occurring in only 11% of responses, but it often results in significant efficacy, with more than a 50% reduction in viability. In contrast, Bliss and IDA occur more frequently but tend to demonstrate lower efficacy.
To better characterize high-efficacy responses—encompassing synergy, Bliss, and IDA—we introduced the concept of “efficacious combination benefit” (ECB). We identified biomarkers of ECB in vitro and found that ECB is a better predictor of response in patient-derived xenografts than synergy alone.
Our study serves as a valuable resource and framework for the preclinical evaluation and development of combination treatments.