title: Levels of target activation predict antifibrotic responses to tyrosine kinase inhibitors.
abstract: OBJECTIVE
  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.affiliation: Department of Rheumatology, University Hospital Zurich, , Zurich, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Maurer
authors.forename: Alfiya
authors.initials: A
authors.lastname: Distler
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Korsa
authors.initials: K
authors.lastname: Khan
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Denton
authors.forename: David
authors.initials: D
authors.lastname: Abraham
authors.forename: Renate E
authors.initials: RE
authors.lastname: Gay
authors.forename: Beat A
authors.initials: BA
authors.lastname: Michel
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: Jörg
authors.initials: J
authors.lastname: Hw Distler
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
mesh_terms: D000328:Adult; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use; D001706:Biopsy; D001761:Bleomycin; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005355:Fibrosis; D051921:Fos-Related Antigen-2 / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D051921:Fos-Related Antigen-2; C497873:Fosl2 protein, mouse; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; C475219:Tsk1 protein, mouse; D001761:Bleomycin; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D017346:Protein Serine-Threonine Kinases; C498826:nilotinib
keywords: Fibroblasts; Systemic Sclerosis; Treatment