Background: Graves' ophthalmopathy (GO) remains hard to treat. Excessive orbital fibroblast activation by platelet-derived growth factor (PDGF)-BB contributes to GO. The tyrosine kinase inhibitors (TKIs) imatinib mesylate and dasatinib both target PDGF-receptor tyrosine kinase activity, albeit with a different potency. We compared the efficacy of these TKIs on PDGF-BB-induced proliferation, and on cytokine and hyaluronan production by orbital fibroblasts. Also the capacity of dasatinib to suppress GO-associated gene expression in orbital tissue was examined. Methods: Orbital fibroblasts from four GO patients and five control subjects were used. The efficacy of the two TKIs was tested by: 1) pre-incubating orbital fibroblasts overnight with different TKI concentrations, followed by 24 h stimulation with PDGF-BB, 2) adding TKI and PDGF-BB simultaneously to the orbital fibroblasts in 24 h cultures. Proliferation was assessed by colorimetric assay. Hyaluronan and cytokine production were measured by ELISA. Furthermore, orbital tissue was obtained from a patient with active GO, and the effect of dasatinib on the expression levels of HAS2-, CCL2-, IL6-, and IL8-mRNA expression was examined by real-time quantitative PCR. Results: Pre-incubation of orbital fibroblasts with imatinib mesylate or dasatinib resulted in significant and dose-dependent inhibition of PDGF-BB-induced orbital fibroblast proliferation, and hyaluronan and cytokine production. Dasatinib exhibited these effects at far lower concentrations. The same results were observed in the setting where TKI and PDGF-BB treatments were commenced simultaneously. In orbital tissue from active GO, dasatinib significantly suppressed HAS2-, CCL2-, IL6- and IL8-mRNA levels. Conclusion: Dasatinib may be a promising alternative to high-dose steroids in the treatment of GO.

Dasatinib, Graves' Ophthalmopathy, Imatinib mesylate, Tyrosine kinase inhibitor,
Graefe's Archive for Clinical and Experimental Ophthalmology
Department of Ophthalmology

Virakul, S, Dalm, V.A.S.H, Paridaens, A.D.A, van den Bosch, W.A, Hirankarn, N, van Hagen, P.M, & Dik, W.A. (2014). The tyrosine kinase inhibitor dasatinib effectively blocks PDGF-induced orbital fibroblast activation. Graefe's Archive for Clinical and Experimental Ophthalmology, 252(7), 1101–1109. doi:10.1007/s00417-014-2674-7