Notch Signaling Activity Determines Uptake and Biological Effect of Imatinib in Systemic Sclerosis Dermal Fibroblasts.

Tyrosine kinase inhibitors have emerged as a therapeutic option for rheumatic diseases such as systemic sclerosis (SSc). Because tyrosine kinases like c-Abl kinase are important for fibroblast activation and fibrosis development in SSc, the c-Abl inhibitor imatinib was proposed for SSc treatment. Transporters for organic cations have become increasingly recognized as an important determinant for uptake and efficacy of tyrosine kinase inhibitors. Therefore, we investigated the role of organic cation transporters in the uptake of imatinib. Moreover, the influence of important SSc pathogenetic factors, like PDGF and Notch pathway activation on these uptake processes, has been studied. We showed that organic cation transporters OCT1-3, novel organic cation transporters OCTN1/2, and the multidrug and toxin extrusion protein MATE1 are expressed in healthy dermal and SSc fibroblasts. Decreased expression levels of MATE1 and decreased imatinib uptake were measured in SSc fibroblasts. In small interfering RNA experiments, MATE1 was identified as key transporter for imatinib uptake and biological effect in dermal fibroblasts. Furthermore, PDGF reduced imatinib uptake by decreasing MATE1 expression in SSc fibroblasts, but not in healthy fibroblasts. Blocking the Notch pathway in SSc fibroblasts increased MATE1 transporter expression and imatinib uptake. In conclusion, MATE1-mediated transport governs therapeutic efficacy of imatinib in SSc.