The kinase inhibitor Sorafenib impairs the antiviral effect of interferon α on hepatitis C virus replication

Recently, it was shown that the kinase inhibitor Sorafenib efficiently blocks HCV replication by inhibition of c-Raf. However, a longer treatment with higher doses of Sorafenib might be associated with adverse effects. Therefore, it was analysed whether a decreased dose of Sorafenib can be applied in combination with interferon alpha to obtain additive antiviral, but at the same time decreased adverse effects. However, Sorafenib abolishes the inhibitory effect of interferon alpha on HCV replication and vice versa. In order to reveal the underlying mechanisms, we observed that on the one hand IFN alpha activates c-Raf and thereby counteracts the inhibitory effect of Sorafenib on HCV replication that is based on the Sorafenib-dependent inhibition of c-Raf. On the other hand we found that the IFN alpha-induced PKR-phosphorylation depends on c-Raf. So, Sorafenib as a potent inhibitor of c-Raf prevents the IFN alpha-dependent PMR phosphorylation. Moreover, Sorafenib inhibits c-Raf-independent the phosphorylation of STAT1 resulting in an impaired induction of IFN alpha-dependent genes. Taken together, these data indicate that a combined application of Sorafenib and interferon alpha in order to obtain an antiviral effect is not useful since Sorafenib exerts an inhibitory effect on targets that are crucial for the transduction of interferon alpha-dependent antiviral response. (C) 2012 Elsevier GmbH. All rights reserved.