Charting the Fragmented Landscape of Drug Synergy. (April 2020) - Meyer, Christian T.
Abstract : Even as the clinical impact of drug combinations continues to accelerate, no consensus on how to quantify drug synergy has emerged. Rather, surveying the landscape of drug synergy reveals the persistence of historical fissures regarding the appropriate domains of conflicting synergy models – fissures impacting all aspects of combination therapy discovery and deployment. Herein we chronicle the impact of these divisions on: (i) the design, interpretation, and reproducibility of high-throughput combination screens; (ii) the performance of algorithms to predict synergistic mixtures; and (iii) the search for higher-order synergistic interactions. Further progress in each of these subfields hinges on reaching a consensus regarding the long-standing rifts in the field. Highlights: Historical rifts between drug synergy paradigms have persisted into the modern era with modern frameworks further dividing the field. These divisions impact the reproducibility of synergy calculations limiting the translational potential of combination studies. Additionally, these divisions undermine the utility of computational approaches to predict synergy. The properties of different synergy metrics have led to contradictory conclusions regarding the existence and nature of higher-order synergistic interactions for increasing numbers of drugs. Unifying the field necessarily precedes a broader acceptance and utilization of synergy calculations for discovering clinically impactful therapeutic mixtures.