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Leukemia. 2010 Apr;24(4):813-20. doi: 10.1038/leu.2009.302. Epub 2010 Jan 28.

Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia.

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1
Section of Molecular Carcinogenesis, Division of Hematology/Oncology, The Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA.

Abstract

Dasatinib is a potent dual Abl/Src inhibitor approved for treatment of Philadelphia chromosome-positive (Ph-positive) leukemias. At a once-daily dose and a relatively short half-life of 3-5 h, tyrosine kinase inhibition is not sustained. However, transient inhibition of K562 leukemia cells with a high-dose pulse of dasatinib or long-term treatment with a lower dose was reported to irreversibly induce apoptosis. Here, the effect of dasatinib on treatment of Bcr/Abl-positive acute lymphoblastic leukemia (ALL) cells was evaluated in the presence of stromal support. Dasatinib eradicated Bcr/Abl ALL cells, caused significant apoptosis and eliminated tyrosine phosphorylation on Bcr/Abl, Src, Crkl and Stat-5. However, treatment of mouse ALL cells with lower doses of dasatinib over an extended period of time allowed the emergence of viable drug-resistant cells. Interestingly, dasatinib treatment increased cell-surface expression of CXCR4, which is important for survival of B-lineage cells, but this did not promote survival. Combined treatment of cells with dasatinib and a CXCR4 inhibitor resulted in enhanced cell death. These results do not support the concept that long-term treatment with low-dose dasatinib monotherapy will be effective in causing irreversible apoptosis in Ph-positive ALL, but suggest that combined treatment with dasatinib and drugs such as AMD3100 may be effective.

PMID:
20111071
PMCID:
PMC3038787
DOI:
10.1038/leu.2009.302
[Indexed for MEDLINE]
Free PMC Article

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