Abstract
Two goals motivate treating diseases with drug combinations: reduce off-target toxicity by minimizing doses (synergistic potency) and improve outcomes by escalating effect (synergistic efficacy). Established drug synergy frameworks obscure such distinction, failing to harness the potential of modern chemical libraries. We therefore developed multi-dimensional synergy of combinations (MuSyC), a formalism based on a generalized, multi-dimensional Hill equation, which decouples synergistic potency and efficacy. In mutant-EGFR-driven lung cancer, MuSyC reveals that combining a mutant-EGFR inhibitor with inhibitors of other kinases may result only in synergistic potency, whereas synergistic efficacy can be achieved by co-targeting mutant-EGFR and epigenetic regulation or microtubule polymerization. In mutant-BRAF melanoma, MuSyC determines whether a molecular correlate of BRAFi insensitivity alters a BRAF inhibitor’s potency, efficacy, or both. These findings showcase MuSyC’s potential to transform the enterprise of drug-combination screens by precisely guiding translation of combinations toward dose reduction, improved efficacy, or both. Meyer et al. developed a framework for measuring drug combination synergy. The framework, termed MuSyC, distinguishes between two types of synergy. The first quantifies the change in the maximal effect with the combination (synergistic efficacy), and the second measures the change in a drug’s potency due to the combination (synergistic potency). By decoupling these two synergies conflated in prior methods, MuSyC rationally guides discovery and translation of drug combinations for the improvement of therapeutic efficacy and reduction of off-target toxicities via dose reduction.
