title: Apoptosis in chronic myeloid leukemia cells transiently treated with imatinib or dasatinib is caused by residual BCR-ABL kinase inhibition.
abstract: 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.
authors: CBIA-Centre for Biomedical Image Analysis, Faculty of Informatics, Masaryk University, Brno, Czech Republic. cbia.muni@gmail.com
authors: Pavel
authors: P
authors: Simara
authors: Stanislav
authors: S
authors: Stejskal
authors: Irena
authors: I
authors: Koutna
authors: David
authors: D
authors: Potesil
authors: Lenka
authors: L
authors: Tesarova
authors: Michaela
authors: M
authors: Potesilova
authors: Zbynek
authors: Z
authors: Zdrahal
authors: Jiri
authors: J
authors: Mayer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D000069439:Dasatinib; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001549:Benzamides; C082869:CRKL protein; D009687:Nuclear Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib