Farnesyltransferase Inhibitors

Farnesylation is the first and most important step in the posttranslational modification of Ras proteins, which are mutated in up to 30-40% of patients with MM.70 Mutated Ras activates Ras-dependent pathways, including the MAPK (mitogen-activated protein kinase) and the PK13 cascades, to form cross-linked complexes that favor cell survival. In preclinical trials, R115777 inhibited the growth and survival of MM cells even in the presence of IL-6.71 In a phase II trial, R115777 was used to treat 43 patients who had previously received treatment for MM. Disease stabilization (defined as 0-25% decrease in the level of paraprotein) occurred in 64% of patients. Fatigue was the most common side effect.72

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