Submitted on October 7, 2005
Revised on November 3, 2005
Accepted on November 7, 2005
Lipid posttranslational modifications: Farnesyl transferase inhibitors
Andrea D. Basso, Paul Kirschmeier, and W. Robert Bishop
Tumor Biology, Schering-Plough, Kenilworth, NJ 07033
Corresponding Author: andrea.basso{at}spcorp.com
Some proteins undergo post-translational modification by addition of an isoprenyl lipid (farnesyl- or geranylgeranyl-isoprenoid) to a cysteine residue proximal to the carboxy-terminus. Protein isoprenylation promotes membrane association and contributes to protein-protein interactions. Farnesylated proteins include small GTPases, tyrosine phosphatases, nuclear lamina, co-chaperones, and centromere-associated proteins. Prenylation is required for transforming activity of Ras. Due to the high frequency of Ras mutations in cancer, farnesyl transferase inhibitors (FTIs) were investigated as a means to antagonize Ras function. Evaluation of FTIs led to the finding that both K- and N-Ras are alternatively modified by GGTase-I in FTI-treated cells. Geranylgeranylated forms of Ras retain the ability to associate with the plasma membrane and activate substrates. Despite this, FTIs are effective at inhibiting growth of human tumor cells in vitro, suggesting activity is dependent on blocking farnesylation of other proteins. FTIs also inhibit the in vivo growth of human tumor xenografts and sensitize these models to chemotherapeutics, most notably taxanes. Several FTIs have entered clinical trials for various cancer indications. In some clinical settings, primarily hematologic malignancies, FTIs have displayed evidence of single-agent activity. Clinical studies in progress are exploring the antitumor activity of FTIs as single-agent and in combination. This review will summarize the basic biology of FTIs, their antitumor activity in preclinical models and the current status of clinical studies with these agents.
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