Heritability of Synergistic Interactions Following Co-Exposure to Anticancer Drugs in Genetically-Diverse Lymphoblastoid Cell Lines

摘要

Real-world exposure scenarios for environmental chemicals or pharmacological drugs often involve significant co-exposure, wherein mixtures of several compounds are involved. However, interindividual responses are most often studied within a single-compound scenario, despite clinical evidence that compounds do not act independently when co-administered. Such synergistic (or antagonistic) effects occur between chemicals when the observed effect of the combination is more (or less) than what would be predicted from the effects of each agent working alone. Modeling synergistic interactions presents challenges in both quantitative modeling and underlying biology. There are a number of statistical methods for modeling synergy from a qualitative perspective, but rigorous quantification and detection of synergy, specifically within drug/chemical mixtures, is limited. Additionally, more investigation is needed into underlying mechanisms of synergistic effects, particularly in regards to potential genetic etiology. We have taken a novel approach to study synergy between chemotherapeutic drugs by applying known methods to show that synergy is heritable in a proven model of cytotoxic response using lymphoblastoid cell lines (LCLs). First, we used the Chou Talalay combination index approach to quantify synergy and results suggest interactions among common chemotherapy drugs. Next, we then used these results to test for a genetic component of variation in synergistic response. Importantly, we identified significant genetic components (> 50% heritability) among several drug combinations. Building on this evidence of a heritable component in synergistic response to co-exposure, we are performing genome wide association studies to identify candidate genes that explain a significant amount of synergistic variation.