Pancreatic cancer is the fourth leading cause of cancer deaths in the USA, afflicting 32,993 Americans annually with a five-year survival rate of only 5.6%. Only by understanding the molecular etiology of this disease can new therapeutic strategies be developed to treat this aggressive cancer. To this end, ~90% of pancreatic tumors contain an oncogenic mutation in the gene KRAS. This is one of, if not the earliest mutation detected in this disease and is well described to experimentally induce pancreatic cancer. Interestingly, the level of oncogenic KRas protein correlates with the degree of tumorigenesis, and clinically it has been shown that the oncogenic potency of KRas mutations tracks with therapeutic responses. In this regard, we discovered that KRas is poorly translated due to an abundance of underrepresented (rare) codons that can impede translation. Moreover, by altering these rare codons to common codons, the tumorigenic potential of KRas was greatly increased in a xenograft model of tumorigenesis. However, ectopic expression of oncogenic KRas can result in more robust or even completely different phenotypes compared to the endogenously expressed oncoprotein, and xenograft models do not recapitulate the spontaneous development of cancer in the pancreas. We therefore propose to knock into the KRas gene an oncogenic version in which rare codons have been changed to common codons. This mutant allele will then be activated in the pancreas, after which the organ will be removed and scored for lesions. Completion of this study will rigorously determine the impact of rare codons on the tumorigenic activity of KRas in a representative animal model of pancreatic cancer, providing the framework to further explore the role of KRas codon bias in pancreatic cancer.
Pancreatic cancer is a devastating disease and only by understanding its molecular etiology can new therapeutic strategies be developed. To this end, pancreatic cancer is commonly driven by a mutation in the gene KRAS. Thus, the proposed studies on oncogenic KRas in pancreatic cancer have direct significance to human health.
|Pershing, Nicole L K; Lampson, Benjamin L; Belsky, Jason A et al. (2015) Rare codons capacitate Kras-driven de novo tumorigenesis. J Clin Invest 125:222-33|