A Consensus Framework for Measuring Drug Synergy

Abstract

Two goals motivate treating diseases with drug combinations: reduce off-target toxicity by minimizing dose (synergistic potency), and improve outcomes by escalating effect (synergistic efficacy). Surprisingly, current drug synergy frameworks do not distinguish between these types of synergy, failing to harness the potential of chemical libraries. We therefore developed Multidimensional Synergy of Combinations (MuSyC), a framework based on a multi-dimensional Hill-equation which recasts synergistic potency and efficacy as extensions of classic pharmacology measures of potency and efficacy for a single drug. By grounding drug synergy calculations in the mathematics of Hill kinetics, MuSyC reveals the previously obscured connection between Bliss Independence and Loewe Additivity, subsuming each into a more general model. Further, the connections between MuSyC and the classic approaches predict systematic biases of Loewe and Bliss which mask synergistic interaction ‒ biases we validate in anti-cancer and anti-malarial combination databases. MuSyC therefore provides a consensus framework for interpreting combination pharmacology and bridges the theoretical void between the often contradictory, traditional drug-synergy paradigms. We applied MuSyC to high-throughput, drug-combination screens in mutant-EGFR lung cancer where we find co-targeting the MAPK pathway only results in synergistic potency, whereas synergistic efficacy is achieved by targeting independent pathways, such as MAPK with epigenetic regulators or microtubule stability. In contrast, we find the combination therapy targeting BRAF and MEK in BRAF-mutant melanoma to be synergistically efficacious, highlighting MuSyC’s utility for investigating disease-specific, drug-class trends in synergy. Finally, we employ MuSyC to decipher a functional genomic screen in combination with a targeted inhibitor in BRAF-mutant melanoma. MuSyC distinguishes the contribution of each molecular species in the kinome to the potency and efficacy of mutant-BRAF inhibition providing a systems view of the critical junctures in BRAF oncogene signaling. These findings showcase MuSyC’s potential to transform the enterprise of drug-combination screens by precisely guiding translation of combinations towards dose reduction, improved efficacy, or both.