Farnesyltransferase inhibitors (FTIs) are among the first 'designer drugs' in clinical trials aimed at blocking cancer cell signal transduction. FTIs were made to attack tumors containing oncogenic Ras, whose function depends upon posttranslational farnesylation. Preclinical trials have demonstrated strikingly specific effects of FTIs against malignantly transformed cells. However, mechanistic investigations have raised doubts that Ras is a necessary target for drug inhibition. Thus, the mechanism of action and identity of FTI target proteins other than Ras have emerged as important questions. Guiding Hypothesis and Specific Aims. We propose to test the hypothesis that FTIs act in part through alteration of Rho prenylation and function (the 'FTI-Rho hypothesis'). Preliminary studies prompt RhoB as a paradigm for study. Cell adhesion and gene activation events related to FTI response and Rho alteration will be investigated. Mechanisms that distinguish apoptosis and cell growth inhibition by FTIs will be defined. In short, we aim to 1) establish Rho as an FTI target, 2) identify Rho-dependent events required to mediate FTI response, and 3) define the factors that dictate growth inhibition versus apoptosis. Innovation and Significance. The main element of innovation in our proposal is the shift of intellectual focus from Ras to Rho as a realm to understand the mechanism of FTI action in cancer cells. Defining FTI mechanism(s) will promote clinical applications as well as novel insights into cancer cell pathophysiology.
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