PT  - JOURNAL ARTICLE
AU  - Dongya Jia
AU  - B. Bishal Paudel
AU  - Corey E. Hayford
AU  - Keisha N. Hardeman
AU  - Herbert Levine
AU  - Jose Onuchic
AU  - Vito Quaranta
TI  - Drug-tolerant idling melanoma cells exhibit theory-predicted metabolic low-low phenotype
AID  - 10.1101/809889
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 809889
4099  - http://biorxiv.org/content/early/2019/10/18/809889.short
4100  - http://biorxiv.org/content/early/2019/10/18/809889.full
AB  - 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 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 should be considered as a target subpopulation for improving MAPKi outcomes in melanoma treatment.Statement of Significance Tumor relapse is almost universal during drug treatment of melanoma patients. Theory coupled with experimentation has uncovered a previously undescribed metabolically inactive state in melanoma upon MAPKi treatment, pointing to novel strategies to prevent relapse.