Farnesyltransferase inhibitors: Overview of their action and role in solid malignancy therapy

Nowadays, molecular targeted cancer therapies represent the core of translational research. Protein prenylation [covalent binding of either a farnesyl (15-C) or a geranylgeranyl (20-C) group to the cysteine residue located in the Tetrapeptide CAAX] is required for the localization and function of different proteins critical to signal transduction pathways and cytoskeleton organization. In this group of molecules we find the Ras proteins. Due to the functional role of Ras farnesylation, farnesyltransferase (FTase) inhibition was thought to be a strategy for interfering with Ras-dependent transformation. When farnesylation is blocked, the function of Ras protein is severely impaired because of the inability of the nonfarnesylated protein to anchor to the membrane. The biology of FTase inhibitors (FTIs) is fascinating since, after substantial investigation and their use in several clinical trials, their exact mechanism of action still remains unclear. In addiction to the RAS ones, FTIs can block the farnesylation of several additional proteins. There are approximately 250 human proteins with literal carboxyl-terminal CAAX motifs (according to Swiss-prot data base). However, most of these contain amino acids at the -AAX positions that make them poor substrates for FTase. At present, several CAAX-containing farnesylated human proteins are currently under investigation as FTIs targets including RhoB, the centromere binding proteins CENP-E and CENP-F, the phosphatase PRL1, 2 and 3, the chaperone protein DnaJ, and Rheb. While the FTIs clearly do not or only partly target Ras, these agents appear to have clinical activity in leukemias and in some solid tumors. This article reviews preclinical and clinical data pertinent to the use of FTIs in solid tumors with special regards to lung cancer where the possible role of FTIs is investigated in the light of possible "translational" trials.