Abstract 623: The activation of EGFR-dependent signaling pathways participates in primary and acquired resistance to sorafenib in hepatoma cells

Context: The multityrosine kinase inhibitor sorafenib is the first and so far only drug to provide overall survival benefit in patients with advanced hepatocellular carcinoma (HCC). Sorafenib blocks the Raf pathway in tumor and endothelial cells as well as VEGFR and PDGFR activation in endothelial cells. Little is known about potential mechanisms that may modify tumor cell sensitivity towards sorafenib. The characterization of such mechanisms could help to alleviate primary or acquired resistance and improve this treatment. Here, we examined whether the activation of EGFR-dependent pathways modulate cell response to sorafenib in responsive or resistant human hepatoma cells. Methods: Five HCC cell lines (HuH7, Hep3B, HepG2, HuH6, PLC/PRF5) were treated with sorafenib alone or in combination with gefitinib, an EGFR TK inhibitor, for up to 72 h. A pool of Hep3B cells resistant to sorafenib (Hep3B-SR) was generated in culture by growing cells in increasing concentrations of sorafenib over a period of several months. Cell viability, DNA synthesis, apoptosis marker expressions (PARP and caspase-3), and pERK/pAKT/cyclin A levels were evaluated. A panel of 42 phosphorylated RTK was analyzed in Hep3B-SR using an antibody array kit (RD 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 623.