Acute dasatinib exposure commits Bcr-Abl-dependent cells to apoptosis

Jennifer L. Snead, Thomas O'Hare, Lauren T. Adrian, Christopher A. Eide, Thoralf Lange, Brian J. Druker, Michael W. Deininger

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46 Scopus citations

Abstract

Pioneering work with the Bcr-Abl inhibitor, imatinib, demonstrated a requirement for constant Bcr-Abl inhibition to achieve maximal therapeutic benefit in treating chronic myeloid leukemia (CML), establishing a paradigm that has guided further drug development for this disease. Surprisingly, the second-generation Bcr-Abl inhibitor, dasatinib, was reported to be clinically effective with once-daily dosing, despite a short (3- to 5-hour) plasma half-life. Consistent with this observation, dasatinib treatment of progenitor cells from chronic-phase CML patients for 4 hours, followed by washout, or continuously for 72 hours both resulted in an induction of apoptosis and a reduction in the number of clonogenic cells. Such acute treatments with clinically achievable dasatinib concentrations also irreversibly committed Bcr-Abl+ CML cell lines to apoptotic cell death. Potent transient Bcr-Abl inhibition using the alternative inhibitor, nilotinib, also resulted in cell death. These findings demonstrate that in vitro assays designed to model in vivo pharmacokinetics can predict clinical efficacy. Furthermore, they challenge the widely held notion that continuous target inhibition is required for optimal efficacy of kinase inhibitors.

Original languageEnglish (US)
Pages (from-to)3459-3463
Number of pages5
JournalBlood
Volume114
Issue number16
DOIs
StatePublished - Nov 19 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Snead, J. L., O'Hare, T., Adrian, L. T., Eide, C. A., Lange, T., Druker, B. J., & Deininger, M. W. (2009). Acute dasatinib exposure commits Bcr-Abl-dependent cells to apoptosis. Blood, 114(16), 3459-3463. https://doi.org/10.1182/blood-2007-10-113969