Increased mutant KRAS gene dosage drives pancreatic cancer progression: evidence for wild-type KRAS as a tumor suppressor?

RAS genes are most commonly associated with gain-of function mutations that promote oncogenic behavior. Activating mutations in KRAS occur in 90–95% cases of pancreatic ductal adenocarcinoma (PDAC) a deadly and highly metastatic disease. Currently the fourth leading cause of cancer death in the United States, PDAC presents with a dismal 5-year survival rate of less than 5% (1). Acquisition of KRAS mutation is regarded as an initiating event in the development of PDAC, but what is the role of the wild-type KRAS allele in disease initiation and progression?