Zhaoyang Fan - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
Liangying Zhang - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
Shaoting Zhang - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
Anbu Liu - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
Shujing Li - 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 - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
Jinhai Tian - 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 - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
Jianmin Sun - NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.

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 PI۳ kinase/AKT pathways plays an important role in KIT mutant-mediated cell transformation. Methods: The frequently seen primary KIT mutations W۵۵۷K۵۵۸del and V۵۶۰D, and the secondary KIT mutations V۶۵۴A and N۸۲۲K, in gastrointestinal stromal tumors were stably transfected into Ba/F۳ 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.

Farnesyltransferase, Imatinib, KIT, RAS.