Drug-tolerant idling melanoma cells exhibit theory-predicted metabolic low-low phenotype

Jia, D.; Paudel, B.; Hayford, C. E.; Hardeman, K.; Levine, H.; Onuchic, J. N.; Quaranta, V.

doi:10.1101/809889

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bioRxiv · 10.1101/809889

Drug-tolerant idling melanoma cells exhibit theory-predicted metabolic low-low phenotype

Jia, D.·Paudel, B.·Hayford, C. E.·Hardeman, K.·Levine, H.·Onuchic, J. N.·Quaranta, V.

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Abstract

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.

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Jia, D., Paudel, B., Hayford, C. E., Hardeman, K., Levine, H., Onuchic, J. N., Quaranta, V.. 2019-10-17. Drug-tolerant idling melanoma cells exhibit theory-predicted metabolic low-low phenotype. https://doi.org/10.1101/809889

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