Dasatinib inhibits the growth of molecularly heterogeneous myeloid leukemias.
Dasatinib inhibits the growth of molecularly heterogeneous myeloid leukemias.
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DOI：
10.1158/1078-0432.ccr-09-2416
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发表时间：
2010-02-15
期刊：
影响因子：
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通讯作者：
Corey SJ
中科院分区：
文献类型：
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作者：
Guerrouahen BS;Futami M;Vaklavas C;Kanerva J;Whichard ZL;Nwawka K;Blanchard EG;Lee FY;Robinson LJ;Arceci R;Kornblau SM;Wieder E;Cayre YE;Corey SJ
Dasatinib is a dual Src/Abl inhibitor, recently approved for Bcr-Abl+ leukemias with resistance or intolerance to prior therapy. Because Src kinases contribute to multiple blood cell functions by triggering a variety of signaling pathways, we hypothesized that their molecular targeting might lead to growth inhibition in acute myeloid leukemia (AML). We studied growth factor-dependent and independent leukemic cell lines, including three cell lines expressing mutants of receptor tyrosine kinases (Flt3 or c-Kit) as well as primary AML blasts for responsiveness to dasatinib. Dasatinib resulted in the inhibition of Src family kinases in all cell lines and blast cells at ~10−9 M. It also inhibited mutant Flt3 or Kit tyrosine phosphorylation at ~10−6 M. Mo7e cells expressing the activating mutation (codon 816) of c-Kit were most sensitive to growth inhibition with a GI50 5×10−9 M. Primary AML blast cells exhibited growth inhibition < 10−6 M. Cell lines which showed growth inhibition at ~10−6 M demonstrated a G1 cell cycle arrest and correlated with accumulation of p21 and p27 protein. Addition of rapamycin or cytotoxic agents enhanced the growth inhibition. Dasatinib also caused the apoptosis of Mo7e cells expressing oncogenic Kit. While all of the precise targets for dasatinib are not known, this multi-kinase inhibitor causes either growth arrest or apoptosis in molecularly heterogeneous AML. Addition of cytotoxic or targeted agents can enhance its effects.
