TY - JOUR
T1 - Effective concentration of a multikinase inhibitor within bone marrow correlates with in vitro cell killing in therapy-resistant chronic myeloid leukemia
AU - Mu, Chaofeng
AU - Wu, Xiaoyan
AU - Ma, Helen
AU - Tao, Wenjing
AU - Zhang, Guodong
AU - Xia, Xiaojun
AU - Shen, Jianliang
AU - Mai, Junhua
AU - Sun, Tong
AU - Sun, Xiaoping
AU - Arlinghaus, Ralph B.
AU - Shen, Haifa
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/5
Y1 - 2016/5
N2 - Leukemia cells escape BCR-ABL-targeted therapy by developing mutations, such as T315I, in the p210BCR-ABL fusion protein in Philadelphia chromosome-positive chronic myeloid leukemia (CML). Although most effort has been focused on development of new tyrosine kinase inhibitors, enrichment of these small-molecule inhibitors in the tumor tissue can also have a profound impact on treatment outcomes. Here, we report that a 2-hour exposure of the T315I-mutant CML cells to 10 mmol/L of the multikinase inhibitor TG101209 suppressed BCR-ABL-independent signaling and caused cell-cycle arrest at G2-M. Further increase in drug concentration to 17.5 μmol/L blocked phosphorylation of the mutant BCR-ABL kinase and its downstream JAK2 and STAT5. The effective dosage to overcome therapy resistance identified in an in vitro setting serves as a guidance to develop the proper drug formulation for in vivo efficacy. A targeted formulation was developed to achieve sustained bone marrow TG101209 concentration at or above 17.5 μmol/L for effective killing of CML cells in vivo. Potent inhibition of leukemia cell growth and extended survival were observed in two murine models of CML treated with 40 mg/kg intravenously administered targeted TG101209, but not with the untargeted drug at the same dosage. Our finding provides a unique approach to develop treatments for therapyresistant CML.
AB - Leukemia cells escape BCR-ABL-targeted therapy by developing mutations, such as T315I, in the p210BCR-ABL fusion protein in Philadelphia chromosome-positive chronic myeloid leukemia (CML). Although most effort has been focused on development of new tyrosine kinase inhibitors, enrichment of these small-molecule inhibitors in the tumor tissue can also have a profound impact on treatment outcomes. Here, we report that a 2-hour exposure of the T315I-mutant CML cells to 10 mmol/L of the multikinase inhibitor TG101209 suppressed BCR-ABL-independent signaling and caused cell-cycle arrest at G2-M. Further increase in drug concentration to 17.5 μmol/L blocked phosphorylation of the mutant BCR-ABL kinase and its downstream JAK2 and STAT5. The effective dosage to overcome therapy resistance identified in an in vitro setting serves as a guidance to develop the proper drug formulation for in vivo efficacy. A targeted formulation was developed to achieve sustained bone marrow TG101209 concentration at or above 17.5 μmol/L for effective killing of CML cells in vivo. Potent inhibition of leukemia cell growth and extended survival were observed in two murine models of CML treated with 40 mg/kg intravenously administered targeted TG101209, but not with the untargeted drug at the same dosage. Our finding provides a unique approach to develop treatments for therapyresistant CML.
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U2 - 10.1158/1535-7163.MCT-15-0577-T
DO - 10.1158/1535-7163.MCT-15-0577-T
M3 - Article
C2 - 26846820
AN - SCOPUS:84969545622
SN - 1535-7163
VL - 15
SP - 899
EP - 910
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 5
ER -