Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis.
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.
Shah
Neil P
NP
Division of Hematology/Oncology, Department of Medicine, UCSF School of Medicine, San Francisco, CA 94143, USA. nshah@medicine.ucsf.edu
Kasap
Corynn
C
Weier
Christopher
C
Balbas
Minna
M
Nicoll
John M
JM
Bleickardt
Eric
E
Nicaise
Claude
C
Sawyers
Charles L
CL
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001549:Benzamides; D045744:Cell Line, Tumor; D002470:Cell Survival; D000069439:Dasatinib; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D066246:ErbB Receptors; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib