Targeting the Rac1 signaling pathway in malignant melanoma

项目摘要/摘要 测序技术的最新进展帮助发现了多种新的恶性肿瘤驱动因素突变 黑色素瘤，包括最近发现的编码鸟嘌呤核苷酸基因的激活突变 交换因子PREX2及其小分子GTP酶底物RAC1。RAC1中的激活突变具有特殊的 感兴趣的是，因为携带这种突变的肿瘤对目前的靶向治疗药物是耐药的。 在很大一部分人类黑色素瘤中存在激活的PREX2和RAC1突变 这种肿瘤很容易受到小分子抑制剂的攻击，这些小分子抑制剂针对的是它的关键激酶效应器，如 A组p21激活的激酶(PAK1、-2和-3)和磷脂酰肌醇-3激酶，特别是PI3Kβ。在……里面 初步研究表明，A组PAK在RAC1的致癌信号转导中起关键作用。 斑马鱼模型和RAC1突变的人黑色素瘤细胞。这些影响形成了特定目标1的基础， 其中我们使用一种新的信号分析方法来建立RAC1，BRAF， 以及NRAS突变的黑素细胞。在目标2中，我们将测试特定的PAK和PI3K小分子抑制剂 它们能够阻断RAC1的影响、生长和生存影响，以及确定可能的药物途径 通过测定药物治疗前后的动态组的活性来确定耐药性。在第三个目标中，我们将 评估一种新的RAC1突变黑色素瘤基因工程小鼠模型，用于临床前研究。 这样的模型将提供一个临床相关的系统来研究RAC1信号在黑素母细胞发育中的作用 以及作为评估黑色素瘤治疗剂的快速测试平台。

PROJECT SUMMARY/ABSTRACT Recent advances in sequencing technology have helped uncover a variety of new driver mutations in malignant melanoma, including recent discoveries of activating mutations in the genes encoding the guanine-nucleotide exchange factor PREX2 and its small GTPase substrate, RAC1. Activating mutations in RAC1 are of special interest, as tumors bearing this mutation are refractory towards current targeted therapeutic agents. The presence of activating PREX2 and RAC1 mutations in a significant fraction of human melanoma suggest that such tumors could be vulnerable to small molecule inhibitors that target its key kinase effectors, such as Group A p21-activated kinases (PAK1, -2, and -3), and phosphatidylinositol-3 kinases, in particular PI3Kβ. In preliminary studies, we have established that Group A PAKs are critical for oncogenic signaling by RAC1 in a zebrafish model and in RAC1-mutant human melanoma cells. These effects form the basis for Specific Aim 1, in which we use a new method for signaling analysis to establish the activity of the entire kinome in RAC1, BRAF, and NRAS-mutant melanocytes. In Aim 2, we will then test specific PAK and PI3K small molecule inhibitors for their ability to block the effects growth and survival effects of RAC1, as well as determine likely pathways of drug resistance by determining the activity of the kinome before and after drug treatment. In the third aim, we will evaluate a new genetically-engineered mouse model of RAC1-mutant melanoma for use in preclinical studies. Such a model will provide a clinically relevant system to study RAC1 signaling in melanoblast development as well as a rapid testing platform to evaluate therapeutic agents in melanoma.