Farnesyl transferase inhibitors: Molecular and cellular mechanisms of anticancer activity

Farnesyl transferase inhibitors (FTIs) have emerged as promising leads in the search for rationally designed anti-cancer therapeutics. These compounds were designed to block the action of oncogenic Ras by inhibiting post-translational modification of the protein. The anti-cancer effects of FTIs have been most dramatically demonstrated in $\nu$-H-Ras transgenic mice, which develop spontaneous cancers. In these animals, FTI treatment leads to almost complete tumor regression Despite this promising finding, however, a number of questions remain concerning the mechanism of action of FTIs. First, the anti-transforming properties of FTIs may result from alteration of proteins other than Ras. Second, it is unclear how FTIs cause tumor regression given that they had not previously been shown to cause cell death in cell culture. Our work investigated these two questions concerning FTI mechanism of action. In the first part of the work, we tested the hypothesis that alteration of RhoB, a small. Ras-related GTPase, is critical to FTI anti-transforming effects. We found that RhoB was both biochemically and functionally altered by FTIs and was essential for Ras transformation. In addition, a myristylated form of RhoB, that was not affected by FTIs, conferred resistance to FTI effects. The second part of this work involved the identification and characterization of an FTI-induced apoptotic response that occurs in cells denied substratum attachment. This finding suggested a potential mechanism for tumor regression in $\nu$-H-ras transgenic mice. In addition, the FTI-induced requirement for adhesion suggests that alteration of Rho-dependent adhesion pathways might be involved in the anti-transforming effects of these compounds