Journal
ONCOTARGET
Volume 6, Issue 14, Pages 12340-12356Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3656
Keywords
c-Met inhibitor; sorafenib; combination; hepatocellular carcinoma
Categories
Funding
- National Natural Science Foundation of china [81371683/H1819, 11104317]
- Medical Technology Major Projects of Wuxi Hospital Center [YGZX1105]
- Clinical Medicine Project of Jiangsu Province [BL2014023]
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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.
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