The Role of RAC1 in Cancer

描述(申请人提供)：肺癌是全球癌症死亡的主要原因。据估计，2006年，仅在美国就有超过16.35万人死于这种疾病。死亡率高的原因是晚期肺癌的检测和诊断以及缺乏有效的晚期肺癌治疗。要确定晚期癌症的治疗方法，我们必须首先了解疾病的分子机制，如果我们要为治疗学的发展确定适当的靶点。肺腺癌中发现的最常见的突变之一是K-ras基因的激活突变，在所有肺腺癌中发现20%-30%。我们已经利用这一知识开发了一种肺腺癌的小鼠模型，该模型与人类肺腺癌的形式非常相似。鉴于Rac家族的小G蛋白在Ras诱导的肿瘤发生中的潜在作用，我们研究了在肺腺癌中Rac家族小G蛋白作为癌基因的潜在功能和对Rac1下游K-ras的需求。Rac小G蛋白是多种信号通路的调节者，包括介导细胞骨架重组、基因表达、内吞作用以及细胞增殖和存活的信号通路。这些途径的解除管制是肿瘤发生学中反复出现的主题。我们的发现表明，在相当大比例的人类肺腺癌中，自然产生的rac1剪接形式上调，并且K-ras诱导的肺肿瘤需要rac1。此外，虽然Rac1的缺失与细胞的存活和增殖是相容的，但当与K-ras在原代上皮细胞中的激活相结合时，Rac1的缺失会导致细胞增殖的显著减少。因此，在表达致癌K-ras的细胞中存在对rac1功能的合成要求。这些研究将有助于阐明肿瘤的发生和发展过程，并加深我们对肺癌分子通路的理解。在K-ras被激活的情况下，rac1的缺失是“致命的”，这一发现增加了这样一种可能性，即在ras突变的肿瘤中靶向rac1在治疗上是有益的，对正常细胞的毒性可能是有限的。公共卫生相关性：建议的研究将阐明肿瘤的发生和发展过程，并增强我们对肺癌分子途径的理解。在K-ras被激活的情况下，rac1b可能作为癌基因发挥作用，而rac1的缺失是“致命的”，这一发现增加了这样一种可能性，即在RAS突变的肿瘤中靶向rac1将在治疗上有益，对正常细胞的毒性可能是有限的。鉴于RAS基因突变在人类癌症中的普遍存在，这些发现可能会对多种癌症产生潜在的影响。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths worldwide. It is estimated that in 2006, more than 163,500 people, in the US alone, will die from this disease. The reasons for the high death rate are detection and diagnosis at advanced stages and a lack of efficient treatments for advanced lung cancer. To identify treatments for advanced stage cancers, we must first understand the molecular mechanisms underlying the disease if we are to identify appropriate targets for the development of therapeutics. One the most common mutations found in lung adenocarcinoma are activating mutations of the K-ras gene, found in 20-30% of all lung adenocarcinomas. We have used this knowledge to develop a mouse model of lung adenocarcinoma that closely recapitulates the human form of the disease. Given the emerging data implicating the small G-proteins of the Rac family in Ras-induced tumorigenesis we examined the potential function of Rac1 as an oncogene and the requirement for Rac1 downstream of K-ras in lung adenocarcinoma. The Rac small G-proteins are regulators of diverse signaling pathways including those mediating cytoskeleton reorganization, gene expression, endocytosis and cell proliferation and survival. The deregulation of these pathways is a reoccurring theme in tumorigenesis. Our findings indicate that a naturally occurring splice form of Rac1 is upregulated in a significant percentage of human lung adenocarcinomas and that Rac1 is required for K- ras induced lung tumors. Furthermore, while Rac1 deletion alone was compatible with cell viability and proliferation, when combined with K-ras activation in primary epithelial cells, loss of Rac1 caused a profound reduction in proliferation. Thus, there is a synthetic requirement for Rac1 function in cells expressing oncogenic K-ras. These studies will shed light on the process of tumor initiation and progression and enhance our understanding of the molecular pathways involved in lung cancer. The finding that loss of Rac1 is "lethal" in the context of activated K-ras raises the possibility that targeting Rac1 in Ras-mutated tumors would be therapeutically beneficial with, perhaps, limited toxicity towards normal cells. PUBLIC HEALTH RELEVANCE: The studies proposed will shed light on the process of tumor initiation and progression and enhance our understanding of the molecular pathways involved in lung cancer. The finding that Rac1b might function as an oncogene and that loss of Rac1 is "lethal" in the context of activated K-ras raises the possibility that targeting Rac1 in Ras- mutated tumors would be therapeutically beneficial with, perhaps, limited toxicity towards normal cells. Given the prevalence of Ras mutations in human cancer these finds could potentially have an impact on a broad spectrum of cancers.