MECHANISM OF FTI ACTION AND K-RAS INHIBITION

(改编自研究人员摘要)法尼基转移酶(FTase) 抑制剂(FTI)阻断对RAS膜至关重要的脂质修饰 缔合和生物学功能，并容易抑制H-RAS转化 体外和动物模型中的活性。因此，FTI正处于紧张的 研究被认为是非常有希望的抗癌治疗方法 探员们。然而，最近的事态发展清楚地表明， FTI行动出人意料地复杂，也不被理解，尽管它 当然包括，尽管它当然包括对FTase的抑制。 在复杂的研究中，发现了优秀的和 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，其高度 抵制FTI行动；FTI对转型的抑制 与K-ras处理抑制无关；以及RAS突变状态 不能预测FTI敏感度。人们普遍认为， 对其中一些发现的可能解释是 非常重要但尚未确定的FTI非RAS目标 行动。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 对意外事件的解释(以及克服的方法) K-RAS对FTIs的高抗性。这一现象的存在和性质 抵抗具有重要的含义，对于我们理解 两种不同法尼基RAS的作用及作用机制 蛋白质在细胞转化和未来成功的药物设计中的作用。 因此，这项提案的总体目标是确定基础 K-RAS对FTI作用的抗性及FTI机制的确定 抑制转化。为达致这些目标，我们建议 确定HIGH对FTI阻力的相对贡献 K-RAS对FTase的亲和力和K-Ras可能的交替预烯基化 RAS在人肿瘤细胞中的表达；比较未处理的相对能力 H-、N-和K-RAS作为显性负离子阻断致癌作用的形式 RAS转化；以及识别其他生理上重要的 FTI的法尼化目标。这些实验的结果将 进一步洞察RAS出人意料的复杂机制 并将提供富有成效的方向 FTIs的改进，以及药物设计的新目标。

(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.