Abstract
Some proteins undergo posttranslational modification by the addition of an isoprenyl lipid (farnesyl- or geranylgeranyl-isoprenoid) to a cysteine residue proximal to the C terminus. Protein isoprenylation promotes membrane association and contributes to protein-protein interactions. Farnesylated proteins include small GTPases, tyrosine phosphatases, nuclear lamina, cochaperones, and centromere-associated proteins. Prenylation is required for the transforming activity of Ras. Because of 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 geranylgeranyl prenyltransferase-1 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 the growth of human tumor cells in vitro, suggesting that activity is dependent on blocking the 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 agents 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.
Highlights
Some proteins undergo posttranslational modification by the addition of an isoprenyl lipid to a cysteine residue proximal to the C terminus
In contrast to lonafarnib and tipifarnib, which result in tumor growth inhibition in most models, BMS-214662 (300–800 mg/kg once daily) induces tumor regression in a broad spectrum of tumor xenograft models, including EJ-1 bladder, MiaPaCa-2 pancreatic, Calu-1 lung, and HT29 and HCT-116 colon tumors [150]
Some single-agent clinical activity was reported in phase I studies in patients with solid tumors, including one partial response in a patient with previously treated metastatic non-small-cell lung cancer (NSCLC) [121] and two NSCLC patients with stable disease for .7 months [175]
Summary
There are three ras genes encoding four Ras proteins (H-Ras, K-Ras4A, K-Ras4B, and N-Ras). Ras activates other signaling pathways, including phosphatidylinositol 3-kinase (PI3K) and Ral-guanine nucleotide exchange factor [46, 47] Activation of these signal transduction pathways by Ras is critical for cell growth and survival. These activating mutations encode Ras proteins with suppressed GTPase activity, allowing Ras to remain in the active GTPbound state independent of upstream activation [19] This results in constitutive signal transduction by GTP-Ras to downstream effectors. Proteins that are not geranylgeranylated in FTItreated cells are more likely to play a critical role in the biological response to FTIs ( it cannot be ruled out that switching of the isoprene content of some proteins results in subtle changes in function) Among these candidate proteins is the H-Ras protein. H-Ras function is completely inhibited by FTIs, and this inhibition may play
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