Figure 1.

MEK inhibition activates mitochondrial oxidative metabolism. (A) Cell sensitivity to the MEK inhibitor trametinib and selumetinib. KRAS-mutant NSCLC cells were treated with trametinib (Tram) or selumetinib (Selu) at gradient concentrations for 72 h, and cell viability was measured. IC₅₀ values are represented as mean ± SEM of three independent experiments with three technical replicates each. Resistant cell lines are marked in green, and sensitive cell lines are marked in brown. (B) Metabolite set enrichment analysis. H460 and A549 cells were treated with trametinib at their respective 1/2 IC₅₀ values for 24 h and then harvested for metabolomic profiling determination. Metabolite set enrichment analysis was performed to identify dysregulated metabolic pathways. The corresponding enrichment pathways (n = 6) are shown. (C) Abundance of major metabolites in the glycolysis and tricarboxylic acid (TCA)-oxidative phosphorylation (OXPHOS) pathways. H460 and A549 cells were exposed to trametinib at their respective 1/2 IC₅₀ values for 24 h. Cell lysates were subjected to LC/MS analysis. Heatmap showed change of metabolites in the glycolysis and the TCA-OXPHOS pathway in trametinib-treated cells versus untreated cells. Metabolite abundance was normalized by cell number. NADH, nicotinamide adenine dinucleotide; NAD⁺, oxidized nicotinamide adenine dinucleotide. Values are scaled as indicated (2 to −2; n = 6).