Background. Farnesyltransferase inhibitors (FTIs) were among the first 'designer drugs' used to block cancer cell signal transduction in clinical trials. Unfortunately, clinical experience to date has not tended to recapitulate the robust efficacy seen in preclinical studies. One potentially important issue is the apparent deficit in FTI cytotoxicity displayed by most human cancer cells as compared to transgenic mouse models. Given the correlation between cytotoxicity and efficacy for most cancer drugs, a key question that emerges is how FTIs kill cells. Studies to address this conceptual gap may cue strategies to leverage clinical utility. In addition, they may expose the mechanisms used by FTI to trigger deaths that are cancer-selective and p53-independent (qualities of wider interest in cancer research) in mice. FTIs were designed initially to target Ras, but significant evidence has accumulated that these agents act beyond Ras. In particular, our laboratory has identified the small GTPase, RhoB, as a critical target that is essential for FTI-induced cell death. Preliminary work identifies potential death effector roles for cyclin B1 and the pro-apoptotic adapter-encoding gene, Binl. These genes are frequently dysregulated in human cancers, perhaps explaining the reduced sensitivity of human cancer cells to FTI cytotoxicity. Guiding Hypothesis and Specific Aims. We hypothesize that farnesyl transferase inhibition triggers cell death by a mechanism that involves RhoB as a primary target and Binl and cyclin B1 as downstream players. Using knock-out and other genetic strategies, we propose to test this hypothesis in established mouse models of breast carcinoma and leukemia, two cancers where FTIs show marked clinical potential. In short, we propose in vivo and in vitro tests to (1) establish the role of these genes in FTI efficacy, and (2) investigate their role and mechanistic relationship in FTI-induced cell death (cytotoxicity). Innovation and Significance. The chief innovations of our proposal are the identification of a Rho-based mechanism for FTI cytotoxicity and potential explanations for attenuated FTI cytotoxicity in many human cancer cells. Candidate effector molecules are defined in this unique mechanism, which we find to be rooted in cancer pathophysiology. By establishing a genetic foundation for FTI-induced cell death, this project offers an opportunity to define surrogate markers to triage cancer patients for FTI treatment and to cue strategies that could enhance FTI efficacy in the majority of patients who are non-responders. Our long-term goal is to understand the basis for FTI cytotoxicity to leverage drug applications in the oncology clinic
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