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The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib
Open accessAbstract
Dasatinib is a small-molecule kinase inhibitor used for the treatment of imatinib-resistant chronic myelogenous leukemia (CML). We have analyzed the kinases targeted by dasatinib by using an unbiased chemical proteomics approach to detect binding proteins directly from lysates of CML cells. Besides Abl and Src kinases, we have identified the Tec kinases Btk and Tec, but not Itk, as major binders of dasatinib. The kinase activity of Btk and Tec, but not of Itk, was inhibited by nanomolar concentrations of dasatinib in vitro and in cultured cells. We identified the gatekeeper residue as the critical determinant of dasatinib susceptibility. Mutation of Thr-474 in Btk to Ile and Thr-442 in Tec to Ile conferred resistance to dasatinib, whereas mutation of the corresponding residue in Itk (Phe-435) to Thr sensitized the otherwise insensitive Itk to dasatinib. The configuration of this residue may be a predictor for dasatinib sensitivity across the kinome. Analysis of mast cells derived from Btk-deficient mice suggested that inhibition of Btk by dasatinib may be responsible for the observed reduction in histamine release upon dasatinib treatment. Furthermore, dasatinib inhibited histamine release in primary human basophils and secretion of proinflammatory cytokines in immune cells. The observed inhibition of Tec kinases by dasatinib predicts immunosuppressive (side) effects of this drug and may offer therapeutic opportunities for inflammatory and immunological disorders.
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“whereas dasatinib, a reversible inhibitor of BTK,23 inhibited nonmutant and mutant BTK with similar efficacy.”
From Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib (2014) · cites this paper as [23]
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Metadata
- Authors
- Hantschel, O., Rix, U., Schmidt, U., Bürckstümmer, T., Kneidinger, M., Schütze, G., Colinge, J., Bennett, K. L., Ellmeier, W., Valent, P., & Superti-Furga, G.
- Affiliations
- Austrian Academy of Sciences (AT)
- Medical University of Vienna (AT)
- *Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 19, 1090 Vienna, Austria;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-08-14
- Volume
- 104
- Issue
- 33
- Pages
- 13283-13288
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1940229
- OpenAlex
- W1991795177
- Cited by
- 284
- References
- 38
- Citations by year
- 2026: 10 · 2025: 4 · 2024: 5 · 2023: 9 · 2022: 8 · 2021: 8 · 2020: 8 · 2019: 10 · 2018: 10 · 2017: 8 · 2016: 7 · 2015: 26 · 2014: 24 · 2013: 33 · 2012: 29
- FWCI
- 14.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Keywords
- dasatinib, Bruton's tyrosine kinase, Tec kinase, ITK, BCR-ABL tyrosine kinase inhibitors, chronic myeloid leukemia, imatinib resistance, kinase inhibitor binding, gatekeeper mutation, kinase inhibitor resistance, mast cells, histamine release, basophils, inflammatory cytokines, immunosuppression, chemoproteomics
- MeSH terms
- Dasatinib, Animals, Basophils, Enzyme-Linked Immunosorbent Assay, Histamine Release, Humans, Mice, Inbred C57BL, Protein-Tyrosine Kinases, Pyrimidines, Thiazoles, Fusion Proteins, bcr-abl, K562 Cells, U937 Cells, Protein Kinase Inhibitors, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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