Journal
CANCER CELL
Volume 14, Issue 6, Pages 485-493Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2008.11.001
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Funding
- Doris Duke Charitable Foundation
- V Foundation
- Edward A. Ageno Leukemia Research Fund
- Sandler Program in Basic Sciences
- Howard Hughes Medical Institute
- Arthur Kern
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The BCR-ABL inhibitor dasatinib achieves clinical remissions in chronic myeloid leukemia (CML) patients using a dosing schedule that achieves potent but transient BCR-ABL inhibition. In vitro, transient potent BCR-ABL inhibition with either dasatinib or imatinib is cytotoxic to CML cell lines, as is transient potent EGFR inhibition with erlotinib in a lung cancer cell line. Cytotoxicity correlates with the magnitude as well as the duration of kinase inhibition. Moreover, cytotoxicity with transient potent target inhibition is equivalent to prolonged target inhibition and in both cases is associated with BIM activation and rescued by BCL-2 overexpression. In CML patients receiving dasatinib once daily, response correlates with the magnitude of BCR-ABL kinase inhibition, thereby demonstrating the potential clinical utility of intermittent potent kinase inhibitor therapy.
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