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Apoptosis in chronic myeloid leukemia cells transiently treated with imatinib or dasatinib is caused by residual BCR–ABL kinase inhibition
Author(s) -
Simara Pavel,
Stejskal Stanislav,
Koutna Irena,
Potesil David,
Tesarova Lenka,
Potesilova Michaela,
Zdrahal Zbynek,
Mayer Jiri
Publication year - 2013
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.23419
Subject(s) - dasatinib , imatinib , myeloid leukemia , tyrosine kinase , cancer research , tyrosine kinase inhibitor , chronic myelogenous leukemia , k562 cells , apoptosis , nilotinib , ponatinib , pharmacology , leukemia , medicine , imatinib mesylate , progenitor cell , chemistry , biology , immunology , stem cell , microbiology and biotechnology , biochemistry , receptor , cancer
Transient, potent BCR–ABL inhibition with tyrosine kinase inhibitors (TKIs) was recently demonstrated to be sufficient to commit chronic myeloid leukemia (CML) cells to apoptosis irreversibly. This mechanism explains the clinical efficacy of once‐daily dasatinib treatment, despite the rapid clearance of the drug from the plasma. However, our in vitro data suggest that apoptosis induction after transient TKI treatment, observed in the BCR–ABL‐positive cell lines K562, KYO‐1, and LAMA‐84 and progenitor cells from chronic phase CML patients, is instead caused by a residual kinase inhibition that persists in the cells as a consequence of intracellular drug retention. High intracellular concentrations of imatinib and dasatinib residues were measured in transiently treated cells. Furthermore, the apoptosis induced by residual imatinib or dasatinib from transient treatment could be rescued by washing out the intracellularly retained drugs. The residual kinase inhibition was also undetectable by the phospho‐CRKL assay. These findings confirm that continuous target inhibition is required for the optimal efficacy of kinase inhibitors. Am. J. Hematol. 88:385–393, 2013. © 2013 Wiley Periodicals, Inc.