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Lck is a key target of imatinib and dasatinib in T-cell activation

Leukemia volume 24, pages 896–900 (2010)Cite this article

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Imatinib (STI-571, Gleevec; Novartis, Basel, Switzerland) is an adenosine-5′-triphosphate (ATP)-competitive tyrosine kinase inhibitor that is highly effective in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. This compound potently inhibits Bcr–Abl, the fusion protein that causes the onset of Philadelphia chromosome-positive chronic myeloid leukemia, and it also inhibits the receptor tyrosine kinases c-KIT and platelet-derived growth factor receptor that have a role in gastrointestinal stromal tumors. Dasatinib (BMS-354825, Sprycel; Bristol-Meyers Squibb, New York, NY, USA) is an ATP-competitor that is structurally unrelated to imatinib and has been approved for the treatment of imatinib-resistant chronic myeloid leukemia. Dasatinib has greater potency against Bcr–Abl and is effective against various imatinib-resistant Bcr–Abl mutants. However, it is also less specific and its range of targets includes the family of Src kinases, whose members have important roles in the growth and differentiation of various cell types.

Both imatinib and dasatinib have been shown to suppress T-cell functions,1, 2, 3, 4, 5 although the reasons for this are not fully established. The intracellular tyrosine kinase Lck is essential for the development and activation of T-cells and previous studies have shown that purified recombinant Lck can be inhibited by dasatinib and imatinib.5, 6 Moreover, a large-scale kinome screen on recombinant kinase domains showed that imatinib binds to Lck, but not to the related Fyn and Src kinases.7 As data obtained with purified proteins do not always translate to in vivo conditions, we set out to validate the selectivity profile of imatinib and dasatinib in a cellular context. We also aimed to obtain novel insights into the T-cell suppressive activities of these drugs and established that dasatinib inhibits T-cell function at clinically relevant concentrations, primarily through inhibition of Lck.

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Acknowledgements

We thank G Mufti (King's College London) for initially providing dasatinib, AI Magee (Imperial College, London) for Lck-GFP cDNA, colleagues W Turnbull for cell sorting, M Lovatt for help with CFSE staining and S John for critically reading the manuscript. This work was supported by a project grant (078170) from The Wellcome Trust to MJ Bijlmakers.

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Author notes

  1. I Ouwehand

    Present address: Current address: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands

  2. A L Giannini

    Present address: Current address: Departamento de Gen,

Authors and Affiliations

  1. Department of Immunobiology, School of Medicine at Guy's, King's College and St Thomas' Hospitals, King's College London, London, UK

    K C Lee, I Ouwehand, A L Giannini & M J Bijlmakers

  2. Department of Haematological Medicine, The Rayne Institute, King's College London, London, UK

    N S Thomas

  3. Institute of Reproductive and Developmental Biology, Imperial College London, London, UK

    N J Dibb

  4. é,

    A L Giannini

  5. tica, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    A L Giannini

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  1. K C Lee
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Correspondence to M J Bijlmakers.

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Lee, K., Ouwehand, I., Giannini, A. et al. Lck is a key target of imatinib and dasatinib in T-cell activation. Leukemia 24, 896–900 (2010). https://doi.org/10.1038/leu.2010.11

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