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Cell Syst. 2019 Feb 27;8(2):97-108.e16. doi: 10.1016/j.cels.2019.01.003. Epub 2019 Feb 20.

Quantifying Drug Combination Synergy along Potency and Efficacy Axes.

Author information

1
Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Center for Cancer Systems Biology at Vanderbilt, Vanderbilt University, Nashville, TN 37232, USA.
2
Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Center for Cancer Systems Biology at Vanderbilt, Vanderbilt University, Nashville, TN 37232, USA.
3
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
4
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Institute of Chemical Biology, High-Throughput Screening Facility, Vanderbilt University, Nashville, TN 37232, USA.
5
Institute of Chemical Biology, High-Throughput Screening Facility, Vanderbilt University, Nashville, TN 37232, USA.
6
Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
7
Center for Cancer Systems Biology at Vanderbilt, Vanderbilt University, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
8
Center for Cancer Systems Biology at Vanderbilt, Vanderbilt University, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: vito.quaranta@vanderbilt.edu.

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.

KEYWORDS:

BRAF-mutant melanoma; drug synergy; high-throughput combination drug screens; non-small-cell lung cancer; systems pharmacology

PMID:
30797775
PMCID:
PMC6675406
[Available on 2020-02-27]
DOI:
10.1016/j.cels.2019.01.003

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