The Use of Molecular Markers in Farnesyltransferase Inhibitor (FTI) Therapy of Breast Cancer

摘要

The hypothesis that pharmacologic inhibitors of Ras can be effective anti-cancer agents has led to the development of Farnesyltransferase inhibitors (FTIs). These agents inhibit the requisite processing of a number of cellular proteins including Ras. FTIs have shown good anti-tumor efficacy and little toxicity in preclinical models and based on these results, numerous clinical trials are currently underway to evaluate the clinical potential of these agents in patients with cancer. However, contrary to the ideas that led to their design, mechanistic studies have not confirmed that they inhibit tumors through the inhibition of Ras. FTIs inhibit the growth of a broad variety of human tumor cells in vitro and studies to date have not identified cellular characteristics that predict the anti-tumor efficacy of this class of agents. We have studied a panel of breast cancer cell lines that differ widely in their sensitivity to FTI in order to determine which molecular characteristics may determine sensitivity to this class of agents. In these cells we find that FTI sensitivity does not correlate with the relative expression of Ras isoforms or the inhibition of Ras processing, growth factor signaling, expression of estrogen receptor or the overexpression of growth factor receptors. Looking for other molecular correlates of FTI sensitivity we have compared the activity of farnesylprotein transferase (FPTase) among these cells and although we find no overall correlation with FTI sensitivity, we find that two cell lines with unusually low FPTase activity are sensitive. Comparing p53 genotype with FTI-sensitivity we find that although most cell lines in our panel have mutant p53, all three cell lines with wild-type p53 are quite sensitive to FTI. In fact, MCF-7 cells which have both wild-type p53 and the lowest FPTase activity are the most FTI-sensitive cell type we have ever seen. Although these studies do not identify any single molecular marker that can accurately predict FTI sensitivity in breast tumors, they highlight the potential roles of FPTase activity and p53 function for further analysis.