Abstract A155: Activation of PI3K/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells

Abstract

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most common and lethal human malignancies. Sorafenib, a tyrosine kinase inhibitor, was recently approved by FDA for HCC. Material and Methods: We established two sorafenib-resistant HCC cell lines (Huh7-R1 and Huh7-R2) from Huh7, a human HCC cell line, by chronic exposure of cells to sorafenib. The mechanisms of resistance were investigated. Results: Sorafenib induced significant apoptosis in Huh7 cells. However, Huh7-R1 and Huh7-R2 showed significant resistance to sorafenib-induced apoptosis at the clinical relevant concentrations (up to 10 M). Thorough comparisons of the molecular changes between Huh7 and resistant cells, we found PI3K/Akt signaling pathways played a significant role in mediating acquired resistance to sorafenib in Huh7-R1 and Huh7-R2 cells. Our data showed that phospho-Akt and p85 (a regulatory subunit of PI3K) were up-regulated, while PTEN was down-regulated in these resistant cells. In addition, ectopic expression of constitutive Akt in Huh7 demonstrated similar resistance to sorafenib. Knocking down Akt by RNA-interference reversed the resistance to sorafenib in Huh7-R1, indicating the importance of Akt in drug sensitivity. Furthermore, the combination of MK-2206, a novel allosteric Akt inhibitor, and sorafenib restored the sensitivity of resistant cells to sorafenib-induced apoptosis. Conclusions: Activation of PI3K/Akt signaling pathway medicates acquired resistance to sorafenib in HCC cells. The combination of sorafenib with MK-2206, an Akt inhibitor, overcomes the resistance at clinical achievable concentrations. This study is supported by NTUH 98P03, NSC 98-3112-B-002-037, DOH (94–98)-TD-B-111-001 and MK-2206 was kindly provided by Merck & Co., Inc. (Whitehouse Station, NJ, USA). Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A155.