Mutant K-Ras-Mediated Oxidative Stress in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the highly lethal cancers with dismal prognosis due to lack of effective targeted therapies and resistance to chemotherapeutic drugs. Significant genetic alterations have been identified as the foremost cause for the instigation and propagation of PDAC, among which K-ras mutations are known as the driver mutation. Oncogenic expression of mutated K-ras results in metabolic changes and altered intracellular signaling pathways that can upsurge the level of cellular reactive oxygen species (ROS). Increase in ROS production further drives the progression of pre-cancerous intraepithelial lesions (PanIN) in pancreas. In order to keep ROS at a level where they are pro-tumorigenic and proliferative but not toxic, antioxidant defense systems are also upregulated in mutant K-ras driven neoplasia. This chapter brings a broad view on mutant K-ras mediated generation of ROS and the mechanisms of overcoming the deleterious effects of ROS through ROS detoxification systems during PDAC tumorigenesis.