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Cited by 202Computational Drug Discovery MethodsLung Cancer Treatments and MutationsMelanoma and MAPK Pathways

Quantifying drug combination synergy along potency and efficacy axes

Open access
Meyer, Christian T., Wooten, David J., Paudel, B. Bishal, Bauer, Joshua, Hardeman, Keisha N., Westover, David, Lovly, Christine M., Harris, Leonard A. +2 more·2019·Cell Systems
DOI 10.1016/j.cels.2019.01.003PMC PMC6675406
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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.

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  • Models requiring multiple doses, such as the Loewe additivity model and response surface-based methods, are not applicable to typical 4-group in vivo combination studies.

    “Models requiring multiple doses are not applicable, such as the Loewe additivity model and the response surface-based methods (18, 38).”

    From Statistical Assessment of Drug Synergy from <i>In Vivo</i> Combination Studies Using Mouse Tumor Models (2023) · cites this paper as [18]

    STAR Methods (Quantification and Statistical Analysis; page not available) calculates Loewe synergy from fitted single-drug dose-response curves and describes fitting combination response surfaces. This supports the need for dose-response data, but the paper does not assess whether these methods are applicable to typical four-group in vivo studies. (LLM, conf=0.82)

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Authors
Meyer, C. T., Wooten, D. J., Paudel, B. B., Bauer, J., Hardeman, K. N., Westover, D., Lovly, C. M., Harris, L. A., Tyson, D. R., & Quaranta, V.
Affiliations
  • Vanderbilt University (US)
  • Vanderbilt-Ingram Cancer Center (US)
Corresponding author
Quaranta, Vito
ORCID
Venue
Cell Systems
Publisher
Elsevier BV
Published
2019-02
Volume
8
Issue
2
Pages
97-108.e16
ISSN
2405-4712 (ISSN-L)
DOI
10.1016/j.cels.2019.01.003
PMC
PMC6675406
OpenAlex
W2917986762
Cited by
202
References
6
Citations by year
2026: 27 · 2025: 31 · 2024: 28 · 2023: 29 · 2022: 33 · 2021: 22 · 2020: 23 · 2019: 9
FWCI
14.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Systems (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Science Foundation
  • National Institutes of Health (U54-CA217450, R01-186193, U01-CA215845, P30-CA086485, R01-CA121210, P01-CA129243)
  • National Cancer Institute (R50-CA211206)
  • Lung Cancer Foundation of America
Topics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords
drug synergy, synergistic efficacy, BRAF inhibitor resistance, kinase inhibitors, epigenetic regulation, microtubule assembly, drug combination screening, dose reduction
MeSH terms
Drug Combinations, Drug Synergism, Humans, Melanoma

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