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• W3117536145 startingPage "e1008538" @default.
• W3117536145 abstract "Combinatorial therapies are required to treat patients with advanced cancers that have become resistant to monotherapies through rewiring of redundant pathways. Due to a massive number of potential drug combinations, there is a need for systematic approaches to identify safe and effective combinations for each patient, using cost-effective methods. Here, we developed an exact multiobjective optimization method for identifying pairwise or higher-order combinations that show maximal cancer-selectivity. The prioritization of patient-specific combinations is based on Pareto-optimization in the search space spanned by the therapeutic and nonselective effects of combinations. We demonstrate the performance of the method in the context of BRAF-V600E melanoma treatment, where the optimal solutions predicted a number of co-inhibition partners for vemurafenib, a selective BRAF-V600E inhibitor, approved for advanced melanoma. We experimentally validated many of the predictions in BRAF-V600E melanoma cell line, and the results suggest that one can improve selective inhibition of BRAF-V600E melanoma cells by combinatorial targeting of MAPK/ERK and other compensatory pathways using pairwise and third-order drug combinations. Our mechanism-agnostic optimization method is widely applicable to various cancer types, and it takes as input only measurements of a subset of pairwise drug combinations, without requiring target information or genomic profiles. Such data-driven approaches may become useful for functional precision oncology applications that go beyond the cancer genetic dependency paradigm to optimize cancer-selective combinatorial treatments." @default.
• W3117536145 created "2021-01-05" @default.
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• W3117536145 date "2020-12-28" @default.
• W3117536145 modified "2023-10-16" @default.
• W3117536145 title "Multiobjective optimization identifies cancer-selective combination therapies" @default.
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• W3117536145 doi "https://doi.org/10.1371/journal.pcbi.1008538" @default.
• W3117536145 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7793282" @default.
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• W3117536145 hasPublicationYear "2020" @default.
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