Ras signaling pathway proteins as therapeutic targets

Ras is a 21 kDa membrane-localized G protein that is coupled to receptor and non-receptor tyrosine kinase activation of downstream cytoplasmic and nuclear events. Mutated ras genes are common, and occur in a wide variety of human malignancies. These activating mutations result in constitutive signaling, thereby stimulating cell proliferation and inhibiting apoptosis. Preclinically, inhibitors of ras signaling revert ras-dependent cellular transformation, and cause regression of ras-dependent rodent tumor xenografts. The ras signaling pathway has therefore attracted considerable attention as a target for anticancer therapy. In this review, novel therapeutic approaches based on the inhibition of ras-mediated signaling, are described. The discussion will be limited to inhibitors which are currently in human clinical trials, and include inhibitors of ras processing, inhibitors of ras protein synthesis and inhibitors of downstream ras effectors.