Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

Tandutinib inhibits FMS receptor signalling, and macrophage and osteoclast formation in vitro

Leukemia volume 22, pages 1452–1453 (2008)Cite this article

Tandutinib (MLN518; CT53518) is a promising quinazoline-based tyrosine kinase inhibitor that is currently in phase II clinical trails for treatment of acute myeloid leukaemia, where it targets the Flt-3 receptor.1 Flt-3 is constitutively activated by internal tandem duplications in up to 30% of acute myelogenous leukemia patients, and a further 5–10% of patients have oncogenic mutations of Asp835 of the kinase domain.2 Flt-3 is closely related to the KIT, PDGF and FMS receptors, and both KIT and PDGF receptors are targets of tandutinib with IC50 values of 170 and 200 nM, respectively, for in vitro kinase assays.3 Here, we report that tandutinib inhibits the FMS receptor for macrophage-colony stimulating factor (M-CSF) with similar effectiveness and also inhibits osteoclastogenesis and macrophage colony formation in vitro. These findings imply that tandutinib may be useful in treating inflammatory and metastatic diseases, including bone metastasis where the FMS receptor is implicated.4, 5, 6

The growth of FDC-P1 cells expressing the oncogenic receptor FMS D802V was unaffected by tandutinib (Figure 1a), which shows that mutation of Asp802 to Val of FMS confers resistance and indicates that tandutinib directly inhibits the wild-type FMS receptor expressed by FDC-P1 cells. This is in accordance with a previous report where the equivalent mutations of D835 of Flt-3 confer resistance to tandutinib.7 As expected, tandutinib suppressed the transformed morphology of rodent fibroblasts caused by the expression of the oncogenic V-Fms receptor (Figures 1b and c).

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1

References

  1. DeAngelo DJ, Stone RM, Heaney ML, Nimer SD, Paquette RL, Klisovic RB et al. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood 2006; 108: 3674–3681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Reilly JT . Class III receptor tyrosine kinases: role in leukaemogenesis. Br J Haematol 2002; 116: 744–757.

    Article  CAS  PubMed  Google Scholar 

  3. Kelly LM, Yu JC, Boulton CL, Apatira M, Li J, Sullivan CM et al. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell 2002; 1: 421–432.

    Article  CAS  PubMed  Google Scholar 

  4. Ohno H, Kubo K, Murooka H, Kobayashi Y, Nishitoba T, Shibuya M et al. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther 2006; 5: 2634–2643.

    Article  CAS  PubMed  Google Scholar 

  5. Murray LJ, Abrams TJ, Long KR, Ngai TJ, Olson LM, Hong W et al. SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis 2003; 20: 757–766.

    Article  CAS  Google Scholar 

  6. Condeelis J, Pollard JW . Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 2006; 124: 263–266.

    Article  CAS  Google Scholar 

  7. Clark JJ, Cools J, Curley DP, Yu JC, Lokker NA, Giese NA et al. Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518. Blood 2004; 104: 2867–2872.

    Article  CAS  Google Scholar 

  8. Brownlow N, Russell AE, Saravanapavan H, Wiesmann M, Murray JM, Manley PW et al. Comparison of nilotinib and imatinib inhibition of FMS receptor signaling, macrophage production and osteoclastogenesis. Leukemia 2007; e-pub ahead of print 13 September 2007.

Download references

Acknowledgements

We thank Millennium Pharmaceuticals for providing tandutinib, and Stephen Marley and Myrtle Gordon for help with the osteoclast assays. We are also grateful to Malcolm Parker, Robert Winston and the IOG Trust for consumable contributions. NB is a recipient of a BBSRC studentship.

Author information

Authors and Affiliations

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

    N Brownlow, M Vaid & N J Dibb

Authors
  1. N Brownlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Vaid
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N J Dibb
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N J Dibb.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brownlow, N., Vaid, M. & Dibb, N. Tandutinib inhibits FMS receptor signalling, and macrophage and osteoclast formation in vitro. Leukemia 22, 1452–1453 (2008). https://doi.org/10.1038/sj.leu.2405085

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2405085

This article is cited by

Search

Advanced search

Quick links