Low glycolytic capacity confers hypersensitivity to YK-135. (A) Gene set enrichment analysis showed decreased canonical glycolysis gene set expression in the EMT-subtype gastric tumor patient cohort (NES = −1.46, P = 0.0481). (B) The graphs represent the correlation between AUC and glycolytic capacity. A Seahorse bioanalyzer assessed the glycolytic capacity in 24 gastric cancer cell lines. r, Spearman correlation coefficient. Spearman correlation test P-value is indicated. (C) YK-135 sensitivity in gastric cancer cell lines with/without glucose supplement. 50% growth inhibition (GI50) was calculated in sensitive (n = 6) and resistant (n = 6) cell lines 72 h-post YK-135 treatment. Unpaired Student’s t test P-value is indicated (n.s.: not significant). (D) Inhibition of glycolysis sensitizes the resistant cell line, MKN45 and NCI-N87 against YK-135 (15.8 μM). Cell lines were treated with a non-lethal concentration of the glycolysis inhibitor 2-deoxyglucose (2-DG, 10 mM) with YK-135 for 72 h. P-values were determined by one-way ANOVA, followed by a Tukey multiple comparison test (**P < 0.01, ***P < 0.001). (E) Graphical summary to describe selective toxicity of YK-135 against EMT-subtype gastric cancer cell lines. The low glycolytic capacity of EMT-subtype gastric cancer cell lines generates synthetic lethality to OXPHOS inhibition.
