Levels of target activation predict antifibrotic responses to tyrosine kinase inhibitors.

Maurer B, Distler A, Dees C, Khan K, Denton CP, Abraham D, Gay RE, Michel BA, Gay S, Distler J, Distler O (2013)

Publication Type: Journal article

Publication year: 2013

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

Book Volume: 72

Pages Range: 2039-46

Journal Issue: 12

DOI: 10.1136/annrheumdis-2013-203729

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.

Authors with CRIS profile

Clara Dees Department of Medicine 3 – Rheumatology and Immunology Jörg Distler Professur für Molekulare Mechanismen der Organfibrose

Involved external institutions

Universitätsspital Zürich (USZ) CH Switzerland (CH) University College London (UCL) GB United Kingdom (GB)

How to cite

APA:

Maurer, B., Distler, A., Dees, C., Khan, K., Denton, C.P., Abraham, D.,... Distler, O. (2013). Levels of target activation predict antifibrotic responses to tyrosine kinase inhibitors. Annals of the Rheumatic Diseases, 72(12), 2039-46. https://doi.org/10.1136/annrheumdis-2013-203729

MLA:

Maurer, Britta, et al. "Levels of target activation predict antifibrotic responses to tyrosine kinase inhibitors." Annals of the Rheumatic Diseases 72.12 (2013): 2039-46.

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