MECHANISM OF FTI ACTION AND K-RAS INHIBITION

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(adapted from the investigator's abstract) Farnesyltransferase (FTase) inhibitors (FTIs) block a lipid modification critical for Ras membrane association and biological function, and easily inhibit H-Ras transforming activity in vitro and in animal models. Therefore, FTIs are under intense investigation as highly promising potential anti-cancer therapeutic agents. However, recent developments have made clear that the mechanism of FTI action is unexpectedly complex and not understood, although it certainly includes, although it certainly includes inhibition of FTase. Among the complexities are the findings that the excellent and straightforward results with H-Ras cannot be extrapolated to K-Ras; that K-Ras, the most commonly mutated form of Ras in human tumors, is highly resistant to FTI action; that FTI inhibition of transformation can be unlinked from inhibition of K-ras processing; and that Ras mutation status is not predictive for FTI sensitivity. There is general agreement that a likely explanation for some of these findings is the existence of critically important but as yet unidentified non-Ras targets of FTI action. However, both the academic and the pharmaceutic research communities are deeply divided over the significance and possible explanations for (and, therefore, of methods to overcome) the unexpectedly high resistance of K-Ras to FTIs. The existence and nature of this resistance has important implication, both for our understanding of the role and mechanism of action of the two different farnesylated Ras proteins in cellular transformation and for future successful drug design. The overall goals of this proposal are, therefore, to determine the basis for K-Ras resistance to FTI action and to determine the mechanism of FTI inhibition of transformation. To accomplish these goals, we propose to determine the relative contributions to FTI resistance of the high affinity of K-Ras for FTase and of possible alternative prenylation of K- Ras in human tumor cells; to compare the relative ability of unprocessed forms of H-, N-, and K-Ras to act as dominant negatives to block oncogenic Ras transformation; and to identify other physiologically important farnesylated targets for FTIs. The results of these experiments will provide further insight into the unexpectedly complex mechanisms of Ras processing and transformation and will provide fruitful directions for improvement in FTIs, as well as novel targets for drug design.