AUTHOR=Jia Dongya , Paudel B. Bishal , Hayford Corey E. , Hardeman Keisha N. , Levine Herbert , Onuchic José N. , Quaranta Vito 

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

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.01426

DOI=10.3389/fonc.2020.01426

ISSN=2234-943X

ABSTRACT=<p>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 <italic>BRAF</italic>-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.</p>