Non-small-cell lung cancer (NSCLC) is the leading cause of cancer related deaths in the world. Oncogenic KRAS (KRASmut) are one of the most common oncogenic mutations in NSCLC cancer, with approximately 40% of lung tumors containing KRASmut. In addition, KRAS mutations predict a poor outcome and a poor response to conventional therapy as well as targeted therapy. As such it is essential we continue to understand the consequences of these mutations. Cancer cells require extensive metabolic reprogramming in order to provide the biomass needed to sustain their proliferative state. Recent studies highlight a role for KRASmut in driving altered cancer metabolism as part of its mechanism of action. A commonly altered metabolic pathway found in many cancers is the hexosamine biosynthetic pathway (HBP). The HBP metabolizes glucose and glutamine to produce UDP-N-acetylglucosamine (UDP-GlcNAc) which is the obligate substrate for O-GlcNAcylation, a carbohydrate post translational modification on cytosolic and nuclear proteins. Levels of O-GlcNAcylation have been shown to be elevated in many cancers including NSCLC. Studies also show that O-GlcNAcylation is often required for tumor growth in vitro and in vivo. I provide preliminary data that KRASmut, but not wildtype KRAS, increases several metabolites in the HBP pathway, most notably, UDP- GlcNAc. I also show that KRASmut increases gene expression of glutamine:-fructose-6-phosphate amidotransferase 2 (GFAT2), the rate limiting enzyme of the HBP pathway. O-GlcNAcylation contributes to metabolic reprogramming in cancer via modification of a variety of transcription factors as well as glycolytic and lipogenic enzymes. A recent study shows O-GlcNAcylation increases expression of lipogenic genes. Increased de novo lipogenesis is an important metabolic alteration in cancer. Lipogenesis provides lipids for biomass, as well as playing an important role in synthesis of bioactive lipids and signal transduction. I show in preliminary data that KRASmut promotes de novo lipogenesis, which is in part required for its ability to promote tumor growth. These previous studies and our preliminary data suggest that KRASmut is driving tumorigenesis by promoting altered cancer metabolism. I hypothesize that KRASmut promotes NSCLC tumor growth via increasing the HBP. I also hypothesize that the HBP pathway in turn activates lipogenesis which leads to increased tumor growth. This hypothesis will be tested by the following specific aims: i) Determine the importance of KRASmut induced HBP in NSCLC and the mechanism(s) responsible and ii) Establish the role of the hexosamine biosynthetic pathway in KRAS mediated increased de novo lipogenesis in NSCLC. The long-term goal of these studies is developing more effective treatment for KRASmut driven NSCLC.
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer related deaths in the world and has a predicted 5 year survival rate of 15.9%. Most lung cancers are caused by accumulating mutations. Oncogenic KRAS are one of the most common oncogenic mutations in lung cancer, with approximately 40% of lung tumors containing KRASmut. Patients harboring the KRAS mutation have a poor prognosis and are resistant to conventional cancer therapy. In this proposal I will investigate a metabolic pathway activated by oncogenic KRAS which will lead to multiple therapeutic targets for future cancer therapy.
