MECHANISM OF FTI ACTION AND K-RAS INHIBITION

（改编自研究者摘要）法尼基转移酶（FTase） 抑制剂（FTIs）阻断Ras膜关键的脂质修饰 结合和生物学功能，并容易抑制H-Ras转化 在体外和动物模型中的活性。因此，FTI在强烈的 作为极具前景潜在抗癌治疗剂的研究 剂.然而，最近的事态发展表明， FTI行动出乎意料地复杂，不被理解，尽管它 当然包括，虽然它肯定包括FTase的抑制。 其中的复杂性是发现，优秀的和 H-Ras的直接结果不能外推到K-Ras; K-Ras是人类肿瘤中最常见的Ras突变形式， 抗FTI作用; FTI对转化抑制可以 与K-ras加工抑制无关; Ras突变状态 不能预测FTI灵敏度。人们普遍认为， 这些发现的可能解释是， FTI中至关重要但尚未确定的非Ras靶点 行动上然而，无论是学术研究还是药学研究， 社区对这一事件的重要性和可能性存在严重分歧， 解释（因此，克服方法）意外 K-Ras对FTIs的高抗性。这件事的存在和性质 抵抗有着重要的意义，无论是对于我们理解 两种不同法尼基化Ras的作用和机制 蛋白质在细胞转化和未来成功的药物设计。 因此，本提案的总体目标是确定 K-Ras对FTI作用的抗性，并确定FTI的机制 抑制转化。为了实现这些目标，我们建议 确定FTI阻力的相对贡献， K-Ras对FTase的亲和力和K-Ras的可能的替代异戊二烯化 Ras在人肿瘤细胞中的作用;比较未处理的 H-、N-和K-Ras形式作为显性阴性物阻断致癌性 Ras转化;并确定其他生理上重要的 FTI的法尼基化靶标。这些实验的结果将 提供了对Ras出乎意料的复杂机制的进一步了解 加工和转化，并将提供富有成效的方向， FTI的改进以及药物设计的新靶点。

(adapted from the investigator's abstract) Farnesyltransferase (FTase) inhibitors (FTIs) block a lipid modification critical for Ras membrane association and biological function, and easily inhibit H-Ras transforming activity in vitro and in animal models. Therefore, FTIs are under intense investigation as highly promising potential anti-cancer therapeutic agents. However, recent developments have made clear that the mechanism of FTI action is unexpectedly complex and not understood, although it certainly includes, although it certainly includes inhibition of FTase. Among the complexities are the findings that the excellent and straightforward results with H-Ras cannot be extrapolated to K-Ras; that K-Ras, the most commonly mutated form of Ras in human tumors, is highly resistant to FTI action; that FTI inhibition of transformation can be unlinked from inhibition of K-ras processing; and that Ras mutation status is not predictive for FTI sensitivity. There is general agreement that a likely explanation for some of these findings is the existence of critically important but as yet unidentified non-Ras targets of FTI action. However, both the academic and the pharmaceutic research communities are deeply divided over the significance and possible explanations for (and, therefore, of methods to overcome) the unexpectedly high resistance of K-Ras to FTIs. The existence and nature of this resistance has important implication, both for our understanding of the role and mechanism of action of the two different farnesylated Ras proteins in cellular transformation and for future successful drug design. The overall goals of this proposal are, therefore, to determine the basis for K-Ras resistance to FTI action and to determine the mechanism of FTI inhibition of transformation. To accomplish these goals, we propose to determine the relative contributions to FTI resistance of the high affinity of K-Ras for FTase and of possible alternative prenylation of K- Ras in human tumor cells; to compare the relative ability of unprocessed forms of H-, N-, and K-Ras to act as dominant negatives to block oncogenic Ras transformation; and to identify other physiologically important farnesylated targets for FTIs. The results of these experiments will provide further insight into the unexpectedly complex mechanisms of Ras processing and transformation and will provide fruitful directions for improvement in FTIs, as well as novel targets for drug design.