1. A cancer drug atlas enables synergistic targeting of independent drug vulnerabilities.
- Author
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Narayan RS, Molenaar P, Teng J, Cornelissen FMG, Roelofs I, Menezes R, Dik R, Lagerweij T, Broersma Y, Petersen N, Marin Soto JA, Brands E, van Kuiken P, Lecca MC, Lenos KJ, In 't Veld SGJG, van Wieringen W, Lang FF, Sulman E, Verhaak R, Baumert BG, Stalpers LJA, Vermeulen L, Watts C, Bailey D, Slotman BJ, Versteeg R, Noske D, Sminia P, Tannous BA, Wurdinger T, Koster J, and Westerman BA
- Subjects
- Animals, Antineoplastic Agents pharmacology, Breast Neoplasms metabolism, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, Computational Biology, Drug Combinations, Glioblastoma metabolism, Humans, Logistic Models, Melanoma metabolism, Drug Synergism
- Abstract
Personalized cancer treatments using combinations of drugs with a synergistic effect is attractive but proves to be highly challenging. Here we present an approach to uncover the efficacy of drug combinations based on the analysis of mono-drug effects. For this we used dose-response data from pharmacogenomic encyclopedias and represent these as a drug atlas. The drug atlas represents the relations between drug effects and allows to identify independent processes for which the tumor might be particularly vulnerable when attacked by two drugs. Our approach enables the prediction of combination-therapy which can be linked to tumor-driving mutations. By using this strategy, we can uncover potential effective drug combinations on a pan-cancer scale. Predicted synergies are provided and have been validated in glioblastoma, breast cancer, melanoma and leukemia mouse-models, resulting in therapeutic synergy in 75% of the tested models. This indicates that we can accurately predict effective drug combinations with translational value.
- Published
- 2020
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