NON-RAS TARGETS OF FARNESYLTRANSFERASE INHIBITORS - FOCUS ON RHO

Farnesyltransferase inhibitors (FTIs) are a novel class of cancer ther apeutics whose development was based on the discovery that the functio n of oncogenic Ras depends upon its posttranslational farnesylation. S ignificantly, experiments in animal models have shown that FTIs have p romise as nontoxic cancer therapeutics. However, cell biological studi es have suggested that FTIs may act at a level beyond that of suppress ing Ras function, so the exact mechanism of action has emerged as a qu estion of major interest. Here, we review evidence that proteins other than Ras are important targets for inhibition, summarize findings sug gesting a role for farnesylated Rho proteins prompted by studies on Rh oB, and suggest a new model for how FTIs exert their biological effect s. The 'FIT-Rho hypothesis' proposes that FTIs act in part by altering Rho-dependent cell adhesion signals which are linked to pathways cont rolling cell cycle and cell survival and which are subverted or defect ive in neoplastic cells. This model offers a novel framework for addre ssing the questions about FTI biology, including the basis for Lack of toxicity to normal cells, cytotoxic verses cytostatic effects on tumo r cells, and the persistence and drug resistance of malignant cells in FTI-treated animals.