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Sensitivity and Resistance to Therapy

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

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.

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Acknowledgements

We thank Reshmi Parameswaran for helpful suggestions and critical reading of the paper. This work was supported by PHS Grants CA090321 (to NH) and R01CA137060 and RO1CA139032 (MM), by funding from a CHLA RCDA, a Jean Perkins Scholar and a StopCancer award (Y-mK); and by a private donor (Y-mK, MM, NH, JG).

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Correspondence to N Heisterkamp.

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Fei, F., Stoddart, S., Müschen, M. et al. Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia. Leukemia 24, 813–820 (2010). https://doi.org/10.1038/leu.2009.302

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