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BRAF-Inhibitor-Induced Metabolic Alterations in A375 Melanoma Cells
Prashant Karki1, Shayne Sensenbach1, Vahideh Angardi1
1Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA.
Abstract:
Acquired drug tolerance has been a major challenge in cancer therapy. Recent evidence has revealed the existence of slow-cycling persister cells that survive drug treatments and give rise to multi-drug-tolerant mutants in cancer. Cells in this dynamic persister state can escape drug treatment by undergoing various epigenetic changes, which may result in a transient metabolic rewiring. In this study, with the use of untargeted metabolomics and phenotype microarrays, we characterize the metabolic profiles of melanoma persister cells mediated by treatment with vemurafenib, a BRAF inhibitor. Our findings demonstrate that metabolites associated with phospholipid synthesis, pyrimidine, and one-carbon metabolism and branched-chain amino acid metabolism are significantly altered in vemurafenib persister cells when compared to the bulk cancer population. Our data also show that vemurafenib persisters have higher lactic acid consumption rates than control cells, further validating the existence of a unique metabolic reprogramming in these drug-tolerant cells. Determining the metabolic mechanisms underlying persister cell survival and maintenance will facilitate the development of novel treatment strategies that target persisters and enhance cancer therapy.
Insights
Cancer persister cells survive drug treatment through epigenetic changes and metabolic rewiring. Vemurafenib persisters show altered metabolism, including higher lactic acid consumption, highlighting unique metabolic reprogramming in drug-tolerant cancer cells.
Area of Science:
- Oncology
- Cancer Biology
- Metabolomics
Background:
- Acquired drug tolerance is a significant hurdle in cancer therapy.
- Slow-cycling persister cells contribute to treatment failure and relapse in cancer.
- These persister cells can evade therapy via epigenetic alterations and metabolic reprogramming.
Purpose of the Study:
- To characterize the metabolic profiles of melanoma persister cells.
- To investigate metabolic changes in cells tolerant to vemurafenib (a BRAF inhibitor).
Main Methods:
- Untargeted metabolomics was employed to analyze metabolic profiles.
- Phenotype microarrays were used to assess cellular phenotypes.
- Comparison of metabolic profiles between vemurafenib persister cells and bulk cancer cells.
Main Results:
- Significant alterations in metabolites related to phospholipid synthesis, pyrimidine metabolism, one-carbon metabolism, and branched-chain amino acid metabolism were observed in persister cells.
- Vemurafenib persister cells exhibited increased lactic acid consumption compared to control cells.
- These findings indicate unique metabolic reprogramming in drug-tolerant melanoma persister cells.
Conclusions:
- Metabolic rewiring is a key mechanism for the survival of drug-tolerant cancer persister cells.
- Understanding these metabolic pathways is crucial for developing targeted therapies against persister cells.
- Targeting persister cell metabolism may enhance the efficacy of cancer treatments.
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