RAS蛋白是具有分子开关作用的小分子GTP酶，在调控细胞的生长、分化、凋亡等重要生命活动中起信号传导作用,RAS异常激活与恶性肿瘤的发生发展密切相关。我们发现RAS棕榈酰化对于其诱导白血病发生是必需的，揭示针对RAS棕榈酰化修饰的靶向干预可能在相关肿瘤治疗方面有效。本课题应用基因敲除及RNA干扰技术研究RAS棕榈酰转移酶（PATs) 的正常生理功能及其在肿瘤发生过程中的作用，揭示RAS-PATs作为疾病治疗靶点的潜能，预测靶向蛋白质棕榈酰化修饰治疗对机体的作用；系统性鉴定RAS-PATs底物，为靶向药物研发策略提供依据；前期研究中，我们还发现了能够选择性杀伤RAS转化细胞的一批具有不同化学核心结构的新小分子化合物。本课题将进一步研究这些小分子化合物对蛋白质棕榈酰化修饰的作用，探索其成为攻克RAS相关肿瘤的可能，为肿瘤的防治提供新的药物作用靶点和新的先导结构，从而为创新药物的发现奠定基础。

RAS proteins are small GTPases that act as molecular switches, transducing signals from many activated receptors that regulate cell proliferation, survival, and differentiation. Hyperactivation of RAS is common in human cancers. Since the enzymatic activity of RAS is used to turn itself off and is inactive in oncogenic RAS, RAS proteins are considered to be "non-targetable" for developing cancer therapies. Identification of alternative targets that block RAS signaling is critical to develop therapies for RAS-related cancer. . The biological activity of RAS proteins relies upon post-translational modifications (PTMs) that anchor RAS to cellular membranes. Protein palmitoylation regulates the membrane targeting, subcellular trafficking, and functions of proteins. We have previously examined the importance of PTMs in NRAS leukemogenesis and found for the first time that palmitoylation is essential for NRAS leukemogenesis. These studies suggest that targeting RAS palmitoylation may be an effective therapy for cancers involving N- and HRAS, which rely on palmitoylation for plasma membrane binding. In addition, although KRAS4B is the more abundant splice variant and does not undergo palmitoylation, a recent study showed that KRAS4A, which relies on palmitoylation for plasma membrane localization, plays an essential role in the development of KRAS-driven lung cancer. This study suggests that targeting palmitoylation may impact on cancers with KRAS mutations as well.. Therapeutic intervention of RAS palmitoylation requires targeting enzymes that mediate RAS palmitoylation. The reaction of RAS palmitoylation is catalyzed by palmitoyl acyltransferases (PATs). Thus far, 24 mammallian PATs, each exhibiting a high degree of enzyme-substrate specificity, have been identified. Yet the physiological role of PATS and their role in tumorigenesis are largely unknown. We hypothesize that RAS-PATs play an important role in RAS transformation and can serve as therapeutic targets for RAS-related cancers. In this proposal, we will examine the role of RAS-PATs in normal physiology and tumorigenesis by using gene knockout and RNAi techenologies; such studies would help to reveal the potential of RAS-PATs as targets for cancer therapies. Like most enzymes, RAS-PATs are likely to have multiple substrates. We will systematically identify substrates of RAS-PATs using proteomic approaches. These studies would help to develop high efficacy and low toxicity therapies. In addition, we have screened a focused library and identified several novel anti-RAS (AR) transformation compounds. We will study the mechanism of these AR compounds in killing RAS transformed cells and identify chemical inhibitors for RAS palmitoylation. These studies would lead to novel therapies, as well as provide tools to investigate the role of palmitoylation in cellular processes.