Review
Tyrosine kinase signaling in fibrotic disorders: Translation of basic research to human disease

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Abstract

Tyrosine kinases regulate a broad variety of physiological cell processes, including metabolism, growth, differentiation and apoptosis. Abnormal tyrosine kinase activity disturbs the physiological cell homeostasis and can lead to cancer, vascular disease, and fibrosis. In regard to fibrosis, different tyrosine kinases have been identified as determinants of disease progression and potential targets for anti-fibrotic therapies. This includes both receptor tyrosine kinases (e.g., PDGF receptor, VEGF receptor, EGF receptor, and JAK kinases) as well as non-receptor tyrosine kinases (e.g., c-Abl, c-Kit, and Src kinases). Given their central role in the pathogenesis of fibrosis, researchers of our field study the anti-fibrotic effects of monoclonal antibodies or small-molecule inhibitors to block the aberrant tyrosine kinase activity and treat fibrosis in preclinical models of various fibrotic diseases (e.g., idiopathic pulmonary fibrosis, renal fibrosis, liver fibrosis, and dermal fibrosis). The results of these studies were promising and prompted clinical trials with different compounds in fibrotic diseases. So far, results from studies with intedanib in idiopathic pulmonary fibrosis and imatinib in idiopathic pulmonary fibrosis and systemic sclerosis have been reported. Although none of these studies reported a positive primary outcome, promising trends in anti-fibrotic efficacy awaken our hopes for a new class of effective anti-fibrotic targeted therapies. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.

Highlights

► Tyrosine kinases are key regulators of fibrotic tissue remodeling. ► Blockade of abnormal tyrosine kinase activity can inhibit experimental fibrosis. ► Trials with the tyrosine kinase inhibitor imatinib in IPF and SSc are inconclusive. ► A large RCT with the tyrosine kinase inhibitor intedanib in IPF is very promising.

Keywords

Tyrosine kinase
Fibrosis
Idiopathic pulmonary fibrosis
Systemic sclerosis
Imatinib
Intedanib

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This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.