Abstract
Sorafenib, an oral multikinase inhibitor of Raf, VEGF and PDGF receptor signaling is approved for advanced hepatocellular carcinoma (HCC). One strategy to improve HCC therapy is to combine agents that target key signaling pathways. Aberrant mesenchymal-epithelial transition factor (c-Met) activation is associated with a variety of human malignancies and therefore represents a target for therapy. In this study, we investigated a novel c-Met inhibitor, DE605, together with sorafenib in hepatocellular carcinoma cells in vitro and in vivo. DE605 and sorafenib synergistically induced apoptosis in hepatocellular carcinoma cells. Mechanistically, DE605 activated the FGFR3/Erk pathway, which in turn was inhibited by sorafenib, resulting in synergism. Finally, DE605 and sorafenib significantly inhibited growth of PLC/PRF/5 hepatocellular carcinoma tumor xenografts in athymic nude mice. Importantly, no obvious weight loss (toxicity) was detected. Thus in combination, DE605 and sorafenib target complementary anti-apoptotic pathways and synergistically suppress HCC, providing the rationale for clinical studies with this novel combination.
Highlights
Hepatocellular carcinoma (HCC) remains a major health problem worldwide as the third cause of cancerrelated mortality and the primary cause of death among cirrhotic patients [1]
We investigated whether DE605 could inhibit c-Met phosphorylation induced in liver cancer cells by different mechanisms
The key signal transduction pathways that have been implicated in the pathogenesis of hepatocellular carcinoma are the EGFR, Ras/Raf/Mek/ Erk, phosphoinositide 3-kinase/Akt, mTOR, hepatocyte growth factor (HGF)/c-Met, Wnt, and Hedgehog signaling cascades [24]
Summary
Hepatocellular carcinoma (HCC) remains a major health problem worldwide as the third cause of cancerrelated mortality and the primary cause of death among cirrhotic patients [1]. Hepatitis B and C, alcohol and aflatoxin have been identified as major risk factors leading to the development of HCC [2, 3]. Curative treatments, such as locoregional ablation, surgical resection, or liver transplantation, are only appropriate for a minority of patients with hepatocellular carcinoma, and their efficacies are limited by high recurrence rates. Sorafenib (Nexavar) is the only drug that has been approved by the U.S Food and Drug Administration (FDA) for patients with advanced hepatocellular carcinoma.
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