Are tyrosine kinase inhibitors promising for the treatment of systemic sclerosis and other fibrotic diseases?
Tissue fibrosis causes organ failure and death in patients with systemic sclerosis (SSc), but clearly effective anti-fibrotic therapies are not available. The tyrosine kinase inhibitor (TKI) imatinib, which blocks the pro-fibrotic c-Abl kinase and PDGF receptor, is currently evaluated in clinical proof-of-concept trials for the treatment of patients with SSc. In experimental models, imatinib efficiently prevented and reduced tissue fibrosis. First clinical case studies demonstrated anti-fibrotic effects of imatinib in selected patients with SSc and other fibrotic diseases, and observational studies in sclerotic chronic graft-versus-host disease showed promising results. Besides imatinib, the two novel TKIs of c-Abl and PDGF receptor nilotinib and dasatinib have recently proven efficacy in experimental models of SSc. The potential of TKIs of the VEGF receptor (e.g., semaxinib, vatalanib, sutent, and sorafenib) and the EGF receptor (e.g., erlotinib, gefitinib, lapatinib, and canertinib) as anti-fibrotic treatments are also discussed in this review. Prior to clinical use, however, controlled trials need to address efficacy as well as tolerability of TKIs in patients with different fibrotic diseases.
Beyer
Christian
C
Department of Internal Medicine 3, University of Erlangen, Nuremberg, Germany.
Distler
Jörg H W
JH
Distler
Oliver
O
D000818:Animals; D001549:Benzamides; D002986:Clinical Trials as Topic; D000069439:Dasatinib; D004195:Disease Models, Animal; D015507:Drugs, Investigational / Q000627:therapeutic use; D066246:ErbB Receptors / Q000235:genetics; D005355:Fibrosis / Q000188:drug therapy*; D006086:Graft vs Host Disease / Q000188:drug therapy; D006801:Humans; D000068877:Imatinib Mesylate; D008947:Mixed Connective Tissue Disease / Q000188:drug therapy; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D011658:Pulmonary Fibrosis / Q000188:drug therapy; D011743:Pyrimidines / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012595:Scleroderma, Systemic / Q000188:drug therapy*; D013844:Thiazoles / Q000037:antagonists & inhibitors / Q000627:therapeutic use*
D001549:Benzamides; D015507:Drugs, Investigational; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D016315:Proto-Oncogene Proteins c-abl; C498826:nilotinib; D000069439:Dasatinib