Resensitizing To Tyrosine Kinase Inhibitor By Inhibiting PFKFB3 In TKI Resistant Chronic Myelogenous Leukemia Cells

Objective: Tyrosine kinase inhibitor(TKI)is the first-line treatment for chronic myeloid leukemia(CML)currently.However,TKIs resistance has been the major obstacle for the CML patients achieving the optimal efficacy for decades.The occurrence and mechanisms of TKI resistance remain incompletely understood.As the intensively activated glycolysis was commonly observed in various types of malignant tumor cells,we tried to explore the correlation between the TKI resistance of CML cells and abnormal glycolytic metabolism in this study,which will hopefully reveal new potential targets for overcoming TKI resistance.Methods: In this study,1 mRNA level of PFKFB3 expression was detected in the mononuclear cell(MNC)of bone marrow from Imatinib-resistant and Imatinibsensitive patients firstly.2 Then,PFKFB3 expression among K562 cells,the K562-derived TKIs-resistant CML cell lines K562 IR and K562 IDR was compared.We next examined how the proliferation curve changed by inhibiting PFKFB3 in the TKI sensitive or resistant cells by PFKFB3 knockdown or PFKFB3 chemical inhibitors.3Allo-transplanted and xeno-tranplanted CML mice were generated to verify the efficacy of the combination of PFKFB3 inhibitors with TKIs in vivo.Results: 1 The expression of PFKFB3 was significantly elevated in the bone marrow cells from Imatinib-resistant patients(P<0.001).2 The expression of PFKFB3 was increased in K562-derived TKIs-resistant CML cell lines compared with K562.PFKFB3 knockdown significantly decreased the proliferation rate of K562,K562 IR and K562 IDR and sensitized TKI-resistant CML cells to TKI inhibition.PFKFB3 inhibitors suppressed proliferation of CML cells,induced cell apoptosis,and enhanced sensitivity to TKI.3 PFKFB3 inhibitors in combination with TKI suppressed TKIsresistant CML cells in vivo and prolonged the survival of allo-transplanted and xenotranplanted CML mice.Conclusion: In this study,potential mechanism of TKI resistant in CML cells was analyzed in terms of glucose metabolism,inhibition of PFKFB3 was confirmed to be able to improve the response of CML resistant cells to TKI.These results provided a novel solution strategy for the TKIs-resistant CML patients.