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.

中文翻译：

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药物耐受的空转黑素瘤细胞表现出理论预测的代谢低-低表型

癌细胞会调整其代谢特性以逃避治疗。代谢适应是复杂的，因此可以通过综合的理论-实验方法更好地理解。使用最小动力学模型，我们预测了以前未描述的低/低（L / L）表型，其特征在于低氧化磷酸化（OXPHOS）和低糖酵解。在这里，我们报道在BRAF中观察到L / L代谢突变的黑色素瘤细胞在长期抑制MAPK（MAPKi）后进入药物耐受的“空转状态”。一致地，使用细胞系和患者样品的可公开获得的RNA测序数据，我们显示黑素瘤细胞在MAPKi上降低了其糖酵解和/或OXPHOS活性，并趋向L / L表型。L / L代谢不利于肿瘤生长，但支持约50％的成功细胞分裂。因此，L / L耐药性的空转细胞是蓄积导致复发的突变的储存库，应被视为改善黑色素瘤治疗中MAPKi结局的靶标亚群。