Quantifying Drug Combination Synergy along Potency and Efficacy Axes
Quantifying Drug Combination Synergy along Potency and Efficacy Axes
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沿着效力和功效轴量化药物组合协同作用沿着
DOI：
10.1016/j.cels.2019.01.003
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发表时间：
2019-02-27
期刊：
影响因子：
9.3
通讯作者：
Quaranta, Vito
中科院分区：
文献类型：
--
作者：
Meyer, Christian T.;Wooten, David J.;Quaranta, Vito
两个目标促使药物组合治疗疾病：通过最小化剂量（协同效力）来减少脱靶毒性，并通过增强效应（协同功效）来改善结果。已建立的药物协同框架掩盖了这种区别，未能利用现代化学库的潜力。因此，我们开发了多维组合协同（MuSyC），这是一种基于广义多维希尔方程的形式主义，它将协同效力和功效解耦。在突变型 EGFR 驱动的肺癌中，MuSyC 揭示了突变型 EGFR 抑制剂与其他激酶抑制剂的组合可能仅产生协同效力，而协同功效可以通过共同靶向突变型 EGFR 和表观遗传调控或微管聚合来实现。在突变 BRAF 黑色素瘤中，MuSyC 确定 BRAFi 不敏感的分子相关性是否会改变 BRAF 抑制剂的效力、功效或两者。这些发现展示了 MuSyC 通过精确指导组合转化以减少剂量、提高疗效或两者兼而有之，从而改变药物组合筛选企业的潜力。
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 multidimensional 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.