Journal
CELL SYSTEMS
Volume 8, Issue 2, Pages 97-+Publisher
CELL PRESS
DOI: 10.1016/j.cels.2019.01.003
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Funding
- National Science Foundation (NSF) Graduate Student Fellowship Program (GRFP) [1445197]
- National Institutes of Health (NIH) [U54-CA217450, R01-186193, U01-CA215845]
- National Cancer Institute (NCI) [R50-CA211206]
- Ruth L. Kirschstein National Research Service Award [2T32HL094296-06A1]
- NIH [P30-CA086485, R01-CA121210, P01-CA129243]
- V Foundation Scholar-in-Training Award
- AACR-Genentech Career Development Award
- Damon Runyon Clinical Investigator Award
- LUNGevity Career Development Award
- Lung Cancer Foundation of America/International Association for the Study of Lung Cancer Lori Monroe Scholarship
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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.
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