Reports of Biochemistry and Molecular Biology

en Farnesyltransferase (FTase) Inhibitors Increase Inhibition of KIT Mutants by Imatinib زیست شناسی ملکولی Molecular Biology مقالات اصلی Original Article <div style="text-align: justify;">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.</div> Farnesyltransferase, Imatinib, KIT, RAS. 74 82 http://rbmb.net/browse.php?a_code=A-10-1197-1&slc_lang=en&sid=1 Zhaoyang Fan 100319475328460017817 100319475328460017817 No NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China. Liangying Zhang 100319475328460017818 100319475328460017818 No NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China. Shaoting Zhang 100319475328460017819 100319475328460017819 No NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China. Anbu Liu 100319475328460017820 100319475328460017820 No NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China. Shujing Li 100319475328460017821 100319475328460017821 No NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China & General Hospital of Ningxia Medical University, Yinchuan, China. Xu Cao 100319475328460017822 100319475328460017822 No NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China. Jinhai Tian 100319475328460017823 100319475328460017823 No NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China & General Hospital of Ningxia Medical University, Yinchuan, China. Sien Zhao 100319475328460017824 100319475328460017824 No NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China. Jianmin Sun jianmin.sun@nxmu.edu.cn 100319475328460017825 100319475328460017825 Yes NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.