farnesyltransferase (ftase) inhibitors increase inhibition of kit mutants by imatinib

Background: mutations in the receptor tyrosine kinase kit are the major cause of gastrointestinal stromal tumors. kit-mediated activation of the ras/raf/mek/erk and pi3 kinase/akt pathways plays an important role in kit mutant-mediated cell transformation.methods: the frequently seen primary kit mutations w557k558del and v560d, and the secondary kit mutations v654a and n822k, in gastrointestinal stromal tumors were stably transfected into ba/f3 cells. cell proliferation was examined with a cck kit, and cell survival and cell cycle were examined by flow cytometry. cell signaling was examined by western blot.results: we found that farnesyltransferase inhibitors tipifarnib and lonafarnib, which inhibit ras activity, inhibited erk activation mediated by both wild-type and kit mutants, which often occur in gastrointestinal stromal tumors. correspondingly, both wild-type and kit mutant-mediated cell survival and proliferation were inhibited by both inhibitors. imatinib is used as the first-line targeted therapy for gastrointestinal stromal tumors in the clinic. in our study, both inhibitors increased imatinib-mediated inhibition of cell survival and proliferation induced by both wild-type and kit mutants. similar to the primary kit mutations, secondary mutations of kit-induced erk activation and cell response were inhibited by both inhibitors.conclusions: our results suggested the potential benefit of farnesyltransferase inhibitors either alone or combined with imatinib in the treatment of gastrointestinal stromal tumors carrying kit mutations.