Drug-Tolerant Idling Melanoma Cells Exhibit Theory-Predicted Metabolic Low-Low Phenotype

Cancer cells adjust their metabolic profiles to evade treatment. Metabolic adaptation is complex and hence better understood by an integrated theoretical-experimental approach. Using a minimal kinetic model, we predicted a previously undescribed Low/Low (L/L) phenotype, characterized by low oxidativ...

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Bibliographic Details
Published in:Frontiers in oncology 2020-08, Vol.10, p.1426-1426
Main Authors: Jia, Dongya, Paudel, B. Bishal, Hayford, Corey E., Hardeman, Keisha N., Levine, Herbert, Onuchic, José N., Quaranta, Vito
Format: Article
Language:English
Subjects:
drug tolerance
idling
low-low
melanoma
metabolism
Oncology
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Summary:Cancer cells adjust their metabolic profiles to evade treatment. Metabolic adaptation is complex and hence better understood by an integrated theoretical-experimental approach. Using a minimal kinetic model, we predicted a previously undescribed Low/Low (L/L) phenotype, characterized by low oxidative phosphorylation (OXPHOS) and low glycolysis. Here, we report that L/L metabolism is observed in BRAF -mutated melanoma cells that enter a drug-tolerant “idling state” upon long-term MAPK inhibition (MAPKi). Consistently, using publicly available RNA-sequencing data of both cell lines and patient samples, we show that melanoma cells decrease their glycolysis and/or OXPHOS activity upon MAPKi and converge toward the L/L phenotype. L/L metabolism is unfavorable for tumor growth, yet supports successful cell division at ~50% rate. Thus, L/L drug-tolerant idling cells are a reservoir for accumulating mutations responsible for relapse, and it should be considered as a target subpopulation for improving MAPKi outcomes in melanoma treatment.
ISSN:2234-943X
2234-943X
DOI:10.3389/fonc.2020.01426