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Levels of target activation predict antifibrotic responses to tyrosine kinase inhibitors
  1. Britta Maurer1,
  2. Alfiya Distler2,
  3. Clara Dees2,
  4. Korsa Khan3,
  5. Christopher P Denton3,
  6. David Abraham3,
  7. Renate E Gay1,
  8. Beat A Michel1,
  9. Steffen Gay1,
  10. Jörg HW Distler2,
  11. Oliver Distler1
  1. 1Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
  2. 2Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany
  3. 3Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School, Royal Free Campus, London, UK
  1. Correspondence to Dr Oliver Distler, Department of Rheumatology, University Hospital Zurich, Gloriastrasse 25, Zurich 8091, Switzerland; oliver.distler{at}usz.ch

Abstract

Objectives To assess whether the discrepancy between the strong antifibrotic effects of tyrosine kinase inhibitors (TKIs) in animal models and the inconsistent results in clinical studies might be related to the activation levels of drug targets.

Methods Skin sections of bleomycin, TSK1, Fra-2 transgenic mice, SSc patients and controls were analysed by histology and immunohistochemistry. Subgroups of mice were treated with the TKIs nilotinib or imatinib. Differences in the activation levels of the TKI targets p-PDGFRβ (platelet derived growth factor β) and p-c-abl were assessed.

Results In bleomycin and TSK1 mice, expression of activated p-PDGFRβ (platelet derived growth factor receptor β) and p-c-abl was ubiquitous with strong upregulation compared with controls. Treatment with TKIs resulted in successful target inhibition and consequently reduced dermal fibrosis. In the Fra-2 model, the activation levels of p-PDGFRβ and p-c-abl were much lower than in the bleomycin and the TSK1 models. Accordingly, nilotinib did not prevent dermal fibrosis and target inhibition was unsuccessful. Notably, in skin biopsies of SSc patients, the mean activation levels of TKI targets were only moderate and in the majority of patients resembled those of the non-responsive Fra-2 model.

Conclusions Animal models for proof-of-concept studies should be selected based on a similar activation level and expression pattern of drug targets as in human SSc.

  • Fibroblasts
  • Systemic Sclerosis
  • Treatment

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