KRAS proteins regulate many cellular processes including initiation of cell division in response to mitogens. Gain of function KRAS mutations appear in approximately 30% of all human cancers and activate effector signal transduction pathways independent of mitogenic stimuli. KRAS driven cancers also frequently have high metabolic rates and may have increased sensitivity to metabolic inhibitors but the underlying mechanism is not fully understood. In this study, we characterized the cellular mechanism of a small molecule inhibitor identified using a transgenic Drosophila melanogaster model that expresses human KRAS-G12V in the fly wing. The compound partially restored wing development in the KRAS-G12V flies and inhibited growth and signal transduction in multiple KRAS driven cancer cells and KRAS-G12V dependent MEF cells but not in MEF cells expressing BRAF-V600E. The compound also had a profound impact on mitochondrial function by inhibiting electron transport (ETC) complex I. Multiple other ETC or ATP synthase inhibitors similarly impaired oncogenic KRAS signal transduction. ATP production through glucose metabolism was sufficient to rescue KRAS function and cellular growth after ETC inhibition, suggesting that inhibition of MAPK signaling is due to low ATP levels rather than a direct consequence of ETC or complex I inhibition. These data indicate that oncogenic KRAS signal transduction requires high cellular ATP levels and suggests a synthetic lethal interaction between KRAS and multiple metabolic targets that could be exploited to target KRAS driven cancers.
Citation Format: Matthew Holderfield, Kanika Sharma. Sensitivity of oncogenic KRAS to adenosine triphosphate suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1365. doi:10.1158/1538-7445.AM2017-1365