Abstract
To elucidate their mechanism of action, inhibitors of Bruton tyrosine kinase (BTK) and resistant BTK mutants were employed to dissect target-dependent cellular functions. BTK-C481S and -T474I, expressed in Ramos and NALM-6 cells, maintained BTK auto-phosphorylation under treatment with ibrutinib or dasatinib, respectively, which showed only modest cytotoxicity. Retained activity of BTK-T474 partially rescued cell migration from inhibition by dasatinib. Importantly, resistant BTK mutants reconstituted B cell receptor-triggered chemokine secretion in the presence of corresponding inhibitors, demonstrating that BTK activity is connected with cell-intrinsic functions of malignant B cells with importance for their dialogue with the micro-environment.
Keywords:
B cell malignancies; chemokine secretion; chemotaxis; resistance mutations; tyrosine kinase inhibitors.
© 2017 John Wiley & Sons Ltd.
MeSH terms
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Adenine / analogs & derivatives
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Agammaglobulinaemia Tyrosine Kinase
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Antineoplastic Agents
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B-Lymphocytes / enzymology*
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Chemokines / metabolism
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Chemotaxis / drug effects
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Dasatinib / administration & dosage
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Dasatinib / pharmacology
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / genetics
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Humans
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Leukemia, B-Cell / enzymology
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Leukemia, B-Cell / genetics*
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Leukemia, B-Cell / pathology
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Lymphoma, B-Cell / enzymology
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Lymphoma, B-Cell / genetics*
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Lymphoma, B-Cell / pathology
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Mutation
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Phosphorylation / drug effects
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Piperidines
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Protein Kinase Inhibitors / pharmacology
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / genetics*
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Protein-Tyrosine Kinases / metabolism
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Pyrazoles / administration & dosage
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Pyrazoles / pharmacology
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Pyrimidines / administration & dosage
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Pyrimidines / pharmacology
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Chemokines
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Piperidines
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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ibrutinib
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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BTK protein, human
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Adenine
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Dasatinib