ETC inhibitors alter oncogenic KRAS signal transduction.

KRAS proteins regulate many cellular processes and gain-of-function KRAS mutations constitutively activate effector signal transduction pathways independent of mitogenic stimuli. Oncogenic KRAS-driven cancers also frequently have high glycolytic rates and may have increased sensitivity to metabolic inhibitors. In this study, we characterize a small molecule found to be active in a drug screen that uses transgenic Drosophila melanogaster expressing human KRASG12V in the wing to assess kRAS suppressing activity. The compound partially restored normal wing development in the KRASG12V flies and inhibited growth and signal transduction in multiple oncogenic KRAS-driven cell lines. It also inhibited Complex 1 of the electron transport chain (ETC). Increased glycolysis or addition of exogenous aspartate was sufficient to rescue KRAS function and cellular growth after ETC inhibition. These data indicate that oncogenic KRAS signal transduction requires high cellular ATP and amino acid biosynthesis and suggest a synthetic lethal interaction between KRAS and metabolic targets. We also describe co-mutations that sensitize KRAS-driven cell lines to OxPhos Inhibition and show how differential OxPhos inhibitor sensitivity in lung and pancreatic cancer cell lines can correlate with low and high glycolysis ssGSEA gene signatures. Citation Format: Kanika Sharma, Ming Yi, Giovanna Grandinetti, Ashish B. Chougule, Philip Liaw, Stephen Yanofsky, Solomon Ungashe, Jeffery H. Thomas, William Garland, Matthew Holderfield. ETC inhibitors alter oncogenic KRAS signal transduction [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B08.