Sorafenib: the gold standard therapy in advanced hepatocellular carcinoma and beyond

Sorafenib is a multikinase inhibitor with inhibitory activity on tyrosine kinases receptors including VEGFR-1, -2, -3, PDGFR-β, Flt-3, RET and c-Kit as well as the RAF serine/threonine kinases (RAF-1, wild-type BRAF and oncogenic B-Raf [V600E]) along the RAS/RAF/MEK/ERK pathway. In particular, sorafenib is a potent in vitro inhibitor of Raf-1 kinase (IC50 of 6 nM/l) and acts on both the wild-type B-Raf (IC50 of 22 nM/l) and the oncogenic B-Raf V600E (IC50 of 38 nM/l). Sorafenib also acts on VEGFR-1 (IC50 of 26 nM/l), VEGFR-2 (IC50 of 90 nM/l), VEGFR-3 (IC50 of 20 nM/l), PDGFR-β (IC50 of 57 nM/l), Flt-3 (IC50 of 58 nM/l), c-Kit (IC50 of 68 nM/l) and RET (IC50 of 43 nM/l). Conversely, sorafenib is not active against a number of kinases including ERK-1, MEK-1, EGFR, HER-2/neu, IGFR-1, c-met, c-yes, PKB, PKA, CDK1/cyclin B, PKCα, PKCγ and PIM-1. Sorafenib inhibits angiogenesis and proliferation and increases apoptosis by blocking VEGFR, PDGFR and the RAS/RAF/MEK/ERK signaling pathway in endothelial cells, pericytes and tumor cells.

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