Farnesyl transferase inhibitors (FTIs) are important anticancer compounds, which are being widely tested for a variety of cancers. They have proven effective against leukemia in phase I/II clinical trials. Experience gained from another target specific drug - STI571/Gleevec indicates that drug resistance is likely to occur due to point mutations in the drug's target.
The aim of this proposal is to investigate the ability of point mutations in farnesyl transferase (FTase) to cause resistance to the FTI SCH66336/Lonafarnib. Specifically, two strategies will be used: a.) random mutagenesis analysis in which a mutated library of FTase will be screened for drug resistance, and b.) site directed mutagenesis of residues in the active site of FTase which are critical drug-binding contacts identified in the co-crystal of the drug bound to enzyme. This will be done to insure the analysis of all critical residues, which were not discovered in the random mutagenesis analysis. We will perform extensive molecular modeling to map the mutations found onto FTase crystal structure to gain insight into the causes of drug resistance. The identification of resistance conferring mutations can help in the design of next generation therapy and in the identification of mutations in patients. A thorough evaluation of these mutations is, thus, critical for the evaluation of this drug.
| Nardi, V; Raz, T; Cao, X et al. (2008) Quantitative monitoring by polymerase colony assay of known mutations resistant to ABL kinase inhibitors. Oncogene 27:775-82 |
| Raz, Tal; Nardi, Valentina; Azam, Mohammad et al. (2007) Farnesyl transferase inhibitor resistance probed by target mutagenesis. Blood 110:2102-9 |
