Abstract 3553: Mutant KRas-mediated AKT2 activation supports lung cancer growth by activating complex II-driven mitochondrial metabolism

Abstract

Abstract Non-small cell lung cancer (NSCLC), the most common type of lung cancer (comprising 80-85 %), is a leading cause of cancer-related death worldwide. KRAS mutation is s major driver oncogene in NSCLC. Constitutive activation of K-Ras via oncogenic mutations plays a key role in development and progression of NSCLC, and is an important target for drug development. Indeed, drugs that target RAF-MAPK and PI3K, the well-established downstream pathways of K-Ras, are being evaluated in the clinic. However, to date, no effective treatments specifically targeting K-Ras have reached the clinic. A new direction for anti-Ras therapies targeting Ras-mediated altered cellular metabolism is implied by recent studies. Hence, as an attempt to investigate novel therapeutic targets to suppress KRAS-driven NSCLC, we assessed metabolic changes in NSCLC cell line and mouse model systems with oncogenic K-Ras mutations. We show that activation of Ras causes metabolic alterations, leading to aerobic glycolysis. Interestingly, despite the changes in the glycolytic pathway, NSCLC cell line and mouse models carrying K-Ras mutation revealed an elevated mitochondrial membrane potential, superoxide production as well as maximal oxygen consumption rate. Moreover, blockade of mitochondrial respiration effectively reduced mutant KRas-driven neoplastic phenotypes in NSCLC cell lines vitro and lung tumor formation in vivo. In contrast, blockade of glycolysis was not effective in the mutant KRas-driven tumorigenic activities. Mechanistically, mutant KRas-mediated activation of Akt2 led to increased expression of succinate dehydrogenase subunit A (SDHA) through increased protein stability by blocking proteasome-mediated degradation, resulting in mitochondrial complex II-dependent respiration. Our study suggests that induction of mitochondrial complex II-dependent respiration is an important mechanism by which oncogenic mutant KRas induces metabolic changes and ROS stress in NSCLC cells, contributing to lung carcinogenesis. Our findings elucidate potential metabolic targets that may provide novel therapeutic strategy for treating NSCLC with oncogenic KRAS mutations. Citation Format: Kwan-Hee Park, Ho-Young Lee. Mutant KRas-mediated AKT2 activation supports lung cancer growth by activating complex II-driven mitochondrial metabolism [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 3553. doi:10.1158/1538-7445.AM2017-3553