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.
Highlights
We explored the impacts of conventional chemotherapeutics on persister metabolism and found that chemotherapeutics induce a transient shift from aerobic glycolysis to oxidative phosphorylation [17]
VEM, which is commonly used in targeted therapy for melanoma with the BRAF V600E-positive mutation, is a competitive inhibitor of the mutated BRAF
We aimed to characterize the metabolic profiles of persisters that are tolerant to vemurafenib, a BRAF inhibitor
Summary
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. 59% of melanomas from a library of cancer cell lines, with the V600E substitution being the most common [4]. The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway is a kinase cascade pathway involved in cell proliferation, in which the BRAF protein activates mitogen-activated protein kinase kinase (MEK or MAPKK) [5]. A mutation in the BRAF protein can lead to uncontrolled cell proliferation and the spread of tumor cells. As the BRAF V600E mutation has been found in over 50% of malignant melanomas [6], BRAF inhibitors, e.g., vemurafenib, are the most common form of therapeutics administered for melanoma treatment
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