Targeting cancer through simultaneous inhibition of key metabolic enzymes

This study explored the potential metabolic vulnerabilities of ovarian cancer cells in comparison to their non-oncogenically transformed precursor cells. A synthetic lethal screen with inhibitors of metabolic pathways showed that simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of tumor cells. While (R)-GNE-140 inhibits lactate dehydrogenase (LDH)A/B and thus effective glycolysis, the BMS-986205 compound, in addition to its known inhibitory activity on Indoleamine 2,3-dioxygenase (IDO1), can also restrict oxidative phosphorylation, as revealed in this study. BMS-986205, which is already in multiple phase III clinical trials, inhibits the Q site of complex I and thus ATP production through mitochondrial respiration. The energetic catastrophe caused by simultaneous interference with glycolysis and oxidative phosphorylation led to cell death or the induction of senescence in tumor cells, with the latter being completely eliminated by senolytics. The occurrence of high synergy upon inhibitor cotreatment was also tested on human colorectal cancer organoids and 119 different tumor cell lines. These experiments revealed highly synergistic activity of the compounds in one third of the tested tumor cell lines, which show statistically significant correlations with alterations in genes with known roles in metabolic regulation. Experiment 1: Transcriptome analysis of KRASG12V/MYC cancer cells comparing 4 hours of (R)-GNE-140 + BMS-986205 combination treatment to 4 hours of DMSO-vehicle control treatment. Experiment 2: Longitudinal transcriptome analysis of KRASG12V/MYC cancer cells over the course of 120 hours GNE+BMS combination treatment.