Concepts in Ras-directed therapy

Ras proteins are key transducers of growth signals regulated by cell surface receptors. They are anchored to the inner surface of the cell membrane where receptor-mediated signalling induces Ras activation (GDP/GTP exchange) and inactivation (stimulation of Ras GTPase activity). Ras-GTP in turn activates a multitude of signalling cascades controlling cell growth and differentiation. Aberrant Ras function (mostly constitutive activation) contributes to the development of many types of neoplastic human diseases. Activating mutations in ras genes, leading to the expression of Ras proteins insensitive to Ras-GTPase activating proteins, are found in as many as 30% of all human tumours. This suggests that Ras is an appropriate target for drug design. Remarkable improvements in the understanding of post-translational modifications in Ras that promote Ras-membrane anchorage, in the mechanisms of activation and inactivation of Ras, and in the interactions of Ras with a plethora of effector molecules have led to the development of new concepts for Ras-directed therapy. The most advanced approach has been that of farnesyltransferase inhibitors (FTIs) designed to inhibit the farnesylation of Ras required for membrane anchorage and transforming activity. FTIs now in clinical trials have been extensively reviewed. Here we review the progress in the development of FTIs and in the development of other promising concepts for Ras-directed therapy. These include compounds such as S-farnesylthiosalicylic acid (FTS), which disrupt the proper anchorage of Ras with the cell membrane and inhibit human tumour growth in animal models, and compounds that interfere with interactions of Ras with its downstream effectors. We conclude with a description of a recently described novel drug concept that could restore the defective GTPase activity of oncogenic Ras and with the interesting results of reovirus-induced tumour regression observed in animal models of human tumours containing an intact Ras signalling pathway.