The Role of RAC1 in Cancer

描述（由申请人提供）：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163，500人死于这种疾病。死亡率高的原因是在晚期发现和诊断以及缺乏对晚期肺癌的有效治疗。为了确定晚期癌症的治疗方法，如果我们要确定开发治疗方法的适当靶点，我们必须首先了解疾病的分子机制。在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，在所有肺腺癌的20-30%中发现。我们已经利用这些知识开发了一种肺腺癌的小鼠模型，该模型非常接近人类形式的肺腺癌。鉴于新出现的数据表明Rac家族的小G蛋白参与Ras诱导的肿瘤发生，我们研究了Rac 1作为癌基因的潜在功能以及肺腺癌中K-ras下游对Rac 1的需求。Rac小G蛋白是多种信号传导途径的调节剂，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那些。这些通路的失调是肿瘤发生中反复出现的主题。我们的研究结果表明，Rac 1的天然剪接形式在相当大比例的人肺腺癌中上调，并且Rac 1是K-ras诱导的肺肿瘤所必需的。此外，虽然Rac 1缺失单独与细胞活力和增殖相容，但当与原代上皮细胞中的K-ras激活相结合时，Rac 1的缺失导致增殖的显著降低。因此，在表达致癌K-ras的细胞中，Rac 1功能是合成的需要。这些研究将揭示肿瘤发生和发展的过程，并增强我们对肺癌分子通路的理解。在激活的K-ras的情况下Rac 1的丢失是“致命的”，这一发现提出了在Ras突变的肿瘤中靶向Rac 1将在治疗上有益的可能性，也许对正常细胞的毒性有限。公共卫生相关性：这些研究将有助于阐明肿瘤发生和发展的过程，并增强我们对肺癌分子通路的理解。Rac 1b可能作为致癌基因发挥作用，Rac 1的缺失在活化的K-ras背景下是“致命的”，这一发现提出了在Ras突变的肿瘤中靶向Rac 1可能在治疗上有益的可能性，可能对正常细胞的毒性有限。鉴于Ras突变在人类癌症中的普遍存在，这些发现可能会对广泛的癌症产生影响。

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.