Evaluating the impact of KRas codon bias on pancreatic cancer

描述(申请人提供)：胰腺癌是美国癌症死亡的第四大原因，每年困扰着32,993名美国人，五年存活率仅为5.6%。只有了解这种疾病的分子病因学，才能开发新的治疗策略来治疗这种侵袭性的癌症。为此，约90%的胰腺肿瘤包含KRAS基因的致癌突变。这是在这种疾病中检测到的最早的突变之一，而且被很好地描述为实验性地诱发胰腺癌。有趣的是，致癌的KRAS蛋白水平与肿瘤的发生程度相关，临床上已经证明KRAS突变的致癌潜能与治疗反应密切相关。在这方面，我们发现KRAS的翻译很差，因为大量的未被充分代表的(稀有)密码子可能会阻碍翻译。此外，通过将这些罕见的密码子改变为普通密码子，KRAS的致瘤潜力在肿瘤发生的异种移植模型中大大增加。然而，与内源性表达的癌蛋白相比，异位表达致癌的KRAS可以导致更强大的表型，甚至完全不同的表型，并且异种移植模型不能概括胰腺癌的自发发展。因此，我们建议在KRAS基因中敲入一种致癌版本，在该版本中，稀有密码子已被改变为普通密码子。然后，这种突变的等位基因将在胰腺中被激活，之后器官将被取出，并对病变进行评分。这项研究的完成将在一个具有代表性的胰腺癌动物模型中严格确定稀有密码子对KRAS致瘤活性的影响，为进一步探讨KRAS密码子偏爱在胰腺癌中的作用提供框架。 公共卫生相关性：胰腺癌是一种毁灭性的疾病，只有了解其分子病因，才能开发新的治疗策略。为此，胰腺癌通常是由KRAS基因突变引起的。因此，胰腺癌致癌因子KRAS的研究对人类健康具有直接意义。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.