Rotblat Barak, Ehrlich Marcello, Haklai Roni, Kloog Yoel
Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Methods Enzymol. 2008;439:467-89. doi: 10.1016/S0076-6879(07)00432-6.
Chronic activation of Ras proteins by mutational activation or by growth factor stimulation is a common occurrence in many human cancers and was shown to induce and be required for tumor growth. Even if additional genetic defects are present, "correction" of the Ras defect has been shown to reverse Ras-dependent tumorigenesis. One way to block Ras protein activity is by interfering with their spatiotemporal localization in cellular membranes or in membrane microdomains, a prerequisite for Ras signaling and biological activity. Detailed reports describe the use of this method in studies employing farnesylthiosalicylic acid (FTS, Salirasib), a Ras farnesylcysteine mimetic, which selectively disrupts the association of chronically active Ras proteins with the plasma membrane. FTS competes with Ras for binding to Ras-escort proteins, which possess putative farnesyl-binding domains and interact only with the activated form of Ras proteins, thereby promoting Ras nanoclusterization in the plasma membrane and robust signals. This chapter presents three-dimensional time-lapse images that track the FTS-induced inhibition of membrane-activated Ras in live cells on a real-time scale. It also describes a mechanistic model that explains FTS selectivity toward activated Ras. Selective blocking of activated Ras proteins results in the inhibition of Ras transformation in vitro and in animal models, with no accompanying toxicity. Phase I clinical trials have demonstrated a safe profile for oral FTS, with minimal side effects and promising activity in hematological malignancies. Salirasib is currently undergoing trials in patients with pancreatic cancer and with nonsmall cell lung cancer, with or without identified K-Ras mutations. The findings might indicate whether with the disruption of the spatiotemporal localization of oncogenic Ras proteins and the targeting of prenyl-binding domains by anticancer drugs is worth developing as a means of cancer treatment.
通过突变激活或生长因子刺激导致的Ras蛋白慢性激活在许多人类癌症中普遍存在，并且已证明其可诱导肿瘤生长且是肿瘤生长所必需的。即使存在其他基因缺陷，Ras缺陷的“纠正”也已证明可逆转Ras依赖性肿瘤发生。阻断Ras蛋白活性的一种方法是干扰其在细胞膜或膜微区中的时空定位，这是Ras信号传导和生物学活性的先决条件。详细报告描述了在使用法尼基硫代水杨酸（FTS，Salirasib）的研究中使用该方法的情况，FTS是一种Ras法尼基半胱氨酸模拟物，可选择性破坏慢性激活的Ras蛋白与质膜的结合。FTS与Ras竞争与Ras护送蛋白的结合，Ras护送蛋白具有假定的法尼基结合结构域，并且仅与Ras蛋白的活化形式相互作用，从而促进质膜中Ras纳米簇的形成和强大的信号。本章展示了三维延时图像，实时跟踪FTS对活细胞中膜激活Ras的抑制作用。它还描述了一个机制模型，解释了FTS对活化Ras的选择性。选择性阻断活化的Ras蛋白可在体外和动物模型中抑制Ras转化，且无伴随毒性。I期临床试验已证明口服FTS具有安全的特征，副作用最小，在血液系统恶性肿瘤中具有有前景的活性。Salirasib目前正在胰腺癌和非小细胞肺癌患者中进行试验，无论是否存在已确定的K-Ras突变。这些发现可能表明破坏致癌Ras蛋白的时空定位以及通过抗癌药物靶向异戊二烯结合结构域作为一种癌症治疗手段是否值得开发。
