Synergistic targeting of ovarian cancer cells through simultaneous inhibition of key metabolic enzymes

Abstract

Despite advances in the therapy of high-grade serous ovarian cancer, overall survival rates remain stagnant, highlighting the need for innovative treatment strategies. In the present study, immortalized fallopian tube secretory epithelial cells were transformed to cancer cells upon expression of KRASG12V and MYC, allowing the side-to-side comparison of an ovarian cancer cell line with its immortalized precursor. A synthetic lethal screen using sublethal concentrations of two inhibitors targeting distinct metabolic pathways showed that the combination of (R)-GNE-140 and BMS-986205 preferentially prevented the proliferation of KRASG12V/MYC cancer cells. While it is known that (R)-GNE-140 prevents lactate fermentation and glycolysis upon inhibition of LDHA/B, the clinically used drug BMS-986205 reportedly inhibits IDO1 and - as revealed in this study - also proper folding of mitochondrial cristae. Accordingly, this study showed that BMS-986205 inhibited oxidative phosphorylation and led to decreased abundance of FAD and succinate, which are important for the activity of electron transport chain complex II. The combination of BMS-986205 (inhibiting oxidative phosphorylation) and (R)-GNE-140 (interfering with regeneration of NAD+ for effective glycolysis) resulted in a decrease of cellular ATP and caused an energetic catastrophe, selectively inducing senescence in KRASG12V/MYC cancer cells. Senescent cancer cells showed increased ß-galactosidase activity, increased ROS production, DNA damage, G2/M cell cycle arrest and the development of the senescence-associated secretory phenotype. These senescent cells were effectively eliminated by apoptosis in the presence of the senolytic compound Dasatinib. In addition to KRASG12V/MYC cancer cells, 16 out of 22 well-established human and murine cancer cell lines were sensitive to the combination treatment. While this synthetic lethal approach demonstrates the feasibility of simultaneously blocking multiple metabolic pathways in cell culture experiments, future studies will determine whether this approach also works in suitable mouse models.