Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants.
Bottom Line: Interestingly, our in vitro study revealed that flumatinib effectively overcame the drug resistance of certain KIT mutants with activation loop mutations (i.e., D820G, N822K, Y823D, and A829P).Our in vivo study consistently suggested that flumatinib had superior efficacy compared with imatinib or sunitinib against 32D cells with the secondary mutation Y823D.Molecular modeling of flumatinib docked to the KIT kinase domain suggested a special mechanism underlying the capability of flumatinib to overcome the drug-resistance conferred by activation loop mutations.
Affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.Show MeSH
Related in: MedlinePlus
Mentions: Furthermore, we evaluated the in vivo efficacy of imatinib, flumatinib, and sunitinib in a survival model in which 32D-V559D or 32D-V559D + Y823D cells were injected s.c. into Balb/cA-nu/nu mice. As shown in Figure 3 (Kaplan–Meier plots), the median survival time for vehicle-treated mice implanted with 32D-V559D cells was 26.5 days. Oral treatments with imatinib (150 mg/kg, q.d. and b.i.d.), flumatinib (75 mg/kg, q.d. and b.i.d.), and sunitinib (50 mg/kg, q.d.) for 14 days prolonged the median survival to 31.5 (imatinib, q.d.; P < 0.001), 36.5 (imatinib, b.i.d.; P < 0.001), 30.5 (flumatinib, q.d.; P < 0.05), 33.5 (flumatinib, b.i.d.; P < 0.001), and 32.5 days (P < 0.001) (Fig. 3), respectively, suggesting that all three drugs are effective against 32D-V559D cells in vivo.
Affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.