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Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants.

Zhao J, Quan H, Xu Y, Kong X, Jin L, Lou L - Cancer Sci. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

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Related in: MedlinePlus

Pharmacokinetic (PK) and pharmacodynamic properties of imatinib, flumatinib, and sunitinib. Mice bearing 32D-V559D + Y823D tumors received a single dose of 150 mg/kg imatinib, 75 mg/kg flumatinib, or 50 mg/kg sunitinib. Mice were killed at different times post-dosing as indicated and the concentrations of imatinib (a), flumatinib (b), and sunitinib (c) were determined in blood plasma and tumor tissue. The phosphorylation levels of KIT, ERK1/2, and signal transducer and activator of transcription-3 (STAT3) in tumors at various times after dosing of imatinib (d), flumatinib (e), sunitinib (f) were determined by Western blotting.
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fig04: Pharmacokinetic (PK) and pharmacodynamic properties of imatinib, flumatinib, and sunitinib. Mice bearing 32D-V559D + Y823D tumors received a single dose of 150 mg/kg imatinib, 75 mg/kg flumatinib, or 50 mg/kg sunitinib. Mice were killed at different times post-dosing as indicated and the concentrations of imatinib (a), flumatinib (b), and sunitinib (c) were determined in blood plasma and tumor tissue. The phosphorylation levels of KIT, ERK1/2, and signal transducer and activator of transcription-3 (STAT3) in tumors at various times after dosing of imatinib (d), flumatinib (e), sunitinib (f) were determined by Western blotting.

Mentions: At 1 h after dosing, the plasma concentration of imatinib achieved 37 483 ng/mL (or 75.94 μM), and the intratumoral imatinib level reached 38 857 ng/g (or 78.72 μM) (Fig. 4a). Thereafter, plasma and intratumoral imatinib concentrations decreased gradually over time (Fig. 4a). These results indicate that imatinib was rapidly absorbed after given orally and achieved peak plasma and intratumoral levels in less than 1 h. In contrast, the plasma flumatinib concentration was highest 2 h after dosing (1073 ng/mL or 1.91 μM), and the intratumoral flumatinib level was highest 4 h after dosing (2721 ng/g or 4.84 μM) (Fig. 4b). For sunitinib, the highest plasma and intratumoral concentrations were achieved 2 and 4 h after dosing, respectively (1098 ng/mL or 2.76 μM, and 21 904 ng/g or 54.97 μM for plasma and tumor, respectively) (Fig. 4c). Intriguingly, our PK data showed that all three agents tended to distribute to the tumors, and this was particularly pronounced for flumatinib and sunitinib (Fig. 4a–c).


Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants.

Zhao J, Quan H, Xu Y, Kong X, Jin L, Lou L - Cancer Sci. (2014)

Pharmacokinetic (PK) and pharmacodynamic properties of imatinib, flumatinib, and sunitinib. Mice bearing 32D-V559D + Y823D tumors received a single dose of 150 mg/kg imatinib, 75 mg/kg flumatinib, or 50 mg/kg sunitinib. Mice were killed at different times post-dosing as indicated and the concentrations of imatinib (a), flumatinib (b), and sunitinib (c) were determined in blood plasma and tumor tissue. The phosphorylation levels of KIT, ERK1/2, and signal transducer and activator of transcription-3 (STAT3) in tumors at various times after dosing of imatinib (d), flumatinib (e), sunitinib (f) were determined by Western blotting.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317885&req=5

fig04: Pharmacokinetic (PK) and pharmacodynamic properties of imatinib, flumatinib, and sunitinib. Mice bearing 32D-V559D + Y823D tumors received a single dose of 150 mg/kg imatinib, 75 mg/kg flumatinib, or 50 mg/kg sunitinib. Mice were killed at different times post-dosing as indicated and the concentrations of imatinib (a), flumatinib (b), and sunitinib (c) were determined in blood plasma and tumor tissue. The phosphorylation levels of KIT, ERK1/2, and signal transducer and activator of transcription-3 (STAT3) in tumors at various times after dosing of imatinib (d), flumatinib (e), sunitinib (f) were determined by Western blotting.
Mentions: At 1 h after dosing, the plasma concentration of imatinib achieved 37 483 ng/mL (or 75.94 μM), and the intratumoral imatinib level reached 38 857 ng/g (or 78.72 μM) (Fig. 4a). Thereafter, plasma and intratumoral imatinib concentrations decreased gradually over time (Fig. 4a). These results indicate that imatinib was rapidly absorbed after given orally and achieved peak plasma and intratumoral levels in less than 1 h. In contrast, the plasma flumatinib concentration was highest 2 h after dosing (1073 ng/mL or 1.91 μM), and the intratumoral flumatinib level was highest 4 h after dosing (2721 ng/g or 4.84 μM) (Fig. 4b). For sunitinib, the highest plasma and intratumoral concentrations were achieved 2 and 4 h after dosing, respectively (1098 ng/mL or 2.76 μM, and 21 904 ng/g or 54.97 μM for plasma and tumor, respectively) (Fig. 4c). Intriguingly, our PK data showed that all three agents tended to distribute to the tumors, and this was particularly pronounced for flumatinib and sunitinib (Fig. 4a–c).

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.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Show MeSH
Related in: MedlinePlus