Ras signaling pathway proteins as therapeutic targets

Ras is a 21 kDa membrane-localized G protein that is coupled to receptor an d non-receptor tyrosine kinase activation of downstream cytoplasmic and nuc lear events. Mutated ras genes are common, and occur in a wide variety of h uman malignancies. These activating mutations result in constitutive signal ing, thereby stimulating cell proliferation and inhibiting apoptosis. Precl inically, inhibitors of ras signaling revert ras-dependent cellular transfo rmation, 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 approache s based on the inhibition of ras-mediated signaling, are described. The dis cussion will be limited to inhibitors which are currently in human clinical trials, and include inhibitors of ras processing, inhibitors of ras protei n synthesis and inhibitors of downstream ras effectors.