Lck is a key target of imatinib and dasatinib in T-cell activation (original) (raw)

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

Subjects

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

References

  1. Blake SJ, Hughes TP, Mayrhofer G, Lyons AB . The Src/ABL kinase inhibitor dasatinib (BMS-354825) inhibits function of normal human T-lymphocytes in vitro. Clin Immunol 2008; 127: 330–339.
    Article CAS PubMed Google Scholar
  2. Cwynarski K, Laylor R, Macchiarulo E, Goldman J, Lombardi G, Melo JV et al. Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro. Leukemia 2004; 18: 1332–1339.
    Article CAS PubMed Google Scholar
  3. Dietz AB, Souan L, Knutson GJ, Bulur PA, Litzow MR, Vuk-Pavlovic S . Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo. Blood 2004; 104: 1094–1099.
    Article CAS PubMed Google Scholar
  4. Schade AE, Schieven GL, Townsend R, Jankowska AM, Susulic V, Zhang R et al. Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Blood 2008; 111: 1366–1377.
    Article CAS PubMed PubMed Central Google Scholar
  5. Seggewiss R, Loré K, Greiner E, Magnusson MK, Price DA, Douek DC et al. Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Blood 2005; 105: 2473–2479.
    Article CAS PubMed Google Scholar
  6. Das J, Chen P, Norris D, Padmanabha R, Lin J, Moquin RV et al. 2-Aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor. J Med Chem 2006; 49: 6819–6832.
    Article CAS PubMed Google Scholar
  7. Fabian MA, Biggs WH, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 2005; 23: 329–336.
    Article CAS PubMed Google Scholar
  8. Giannini A, Bijlmakers MJ . Regulation of the Src family kinase Lck by Hsp90 and ubiquitination. Mol Cell Biol 2004; 24: 5667–5676.
    Article CAS PubMed PubMed Central Google Scholar
  9. Thomas J, Wang L, Clark RE, Pirmohamed M . Active transport of imatinib into and out of cells: implications for drug resistance. Blood 2004; 104: 3739–3745.
    Article CAS PubMed Google Scholar
  10. Sillaber C, Herrmann H, Bennett K, Rix U, Baumgartner C, Bohm A et al. Immunosuppression and atypical infections in CML patients treated with dasatinib at 140 mg daily. Eur J Clin Invest 2009; 39: 1098–1109.
    Article CAS PubMed Google Scholar
  11. Chen J, Schmitt A, Chen B, Rojewski M, Rubeler V, Fei F et al. Nilotinib hampers the proliferation and function of CD8+ T lymphocytes through inhibition of T cell receptor signalling. J Cell Mol Med 2008; 12: 2107–2118.
    Article CAS PubMed PubMed Central Google Scholar

Download references

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.

Author information

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

Authors

  1. K C Lee
    You can also search for this author inPubMed Google Scholar
  2. I Ouwehand
    You can also search for this author inPubMed Google Scholar
  3. A L Giannini
    You can also search for this author inPubMed Google Scholar
  4. N S Thomas
    You can also search for this author inPubMed Google Scholar
  5. N J Dibb
    You can also search for this author inPubMed Google Scholar
  6. M J Bijlmakers
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toM J Bijlmakers.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

About this article

Cite this article

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

Download citation

This article is cited by