HGF-induced MET Activation Leads To IGF-1R Inhibitor NVP-AEW541 Resistance In Gastrointestinal Cancer Cells

BackgroundIGF-1R overexpression or activation was observed in a panel of tumors, which promotes tumor development, invasion, migration and anti-apoptosis, making IGF-1R a promising taget of cancer treatment. Although several early phase clinical trials of insulin-like growth factor â…  receptor (IGF-1 R)-specific antibodies for cancer treatment are impressive, initial phase â…¢ results in unselected patients have been disappointing, due to unidentified biomarker and drug resistance. Our research aims at exploring the mechanism of hepatocyte growth factor (HGF)-induced MET activation leading to IGF-1R tyrosine kinase inhibitor NVP-AEW541 resistance in gastrointestinal cancer cells, which may benefit further clinical studies.MethodsNCI-N87 and HCT-116 cells were treated with varying concentrations and combinations of NVP-AEW541, HGF and crizotinib. Biological end points included proliferation and cell apoptosis. Receptor activation and downstream signaling pathway were examined to explore the resistance mechanism.ResultsMET-overexpressed MKN-45 cell showed the most unresponsiveness to IGF-1R inhibitor NVP-AEW541. HGF-induced MET activation leads to NVP-AEW541 resistance in gastrointestinal cancer cells by activating shared downstream AKT pathways, and inhibition of MET using crizotinib prevents MET-dependent activation of AKT and MAPK. Furthermore, combination therapy of NVP-AEW541 and crizotinib shows synergistic anti-tumor effect in vitro.ConclusionsHGF-induced MET activation leads to NVP-AEW541 resistance in gastrointestinal cancer cells. A rational combination of tyrosine kinase inhibitors which raises hope for overcoming resistance to mono-agent therapy merits further investigation.