Cabozantinib and Tivantinib, but not INC280, Induce Anti-Proliferative and Anti-Migratory Effects in Human Neuroendocrine Tumour Cells in vitro: Evidence for ‘Off-Target' Effects not Mediated by c-Met Inhibition

Background/Aims: The hepatocyte growth factor (HGF)/transmembrane tyrosine kinase receptor c-Met has been defined as a potential target in antitumoural treatment of various carcinomas. We aimed to investigate the direct effect of c-Met inhibition on neuroendocrine tumour cells in vitro. Methods: The effects of the multi-tyrosine-kinase inhibitors cabozantinib and tivantinib and of the highly specific c-Met inhibitor INC280 were investigated in human pancreatic neuroendocrine BON1, bronchopulmonary NCI-H727 and midgut GOT1 cells in vitro. Results: INC280, cabozantinib and tivantinib inhibited c-Met phosphorylation, respectively. However, while equimolar concentrations (10 uM) of cabozantinib and tivantinib inhibited cell viability and cell migration, INC280 had no inhibitory effect. Knockdown experiments with c-Met siRNA also did not demonstrate effects on cell viability. Cabozantinib and tivantinib caused a G2 arrest in neuroendocrine tumor cells. Conclusions: Our in vitro data suggest that c-Met inhibition alone is not sufficient to exert direct antitumoural or antimigratory effects in neuroendocrine tumour cells. The multi-tyrosine-kinase inhibitors cabozantinib and tivantinib show promising antitumoural and antimigratory effects in neuroendocrine tumour cells, which are most probably ‘off-target' effects, not mediated by c-Met.