TY - JOUR
T1 - Cabozantinib and Tivantinib, but not INC280, Induce Anti-Proliferative and Anti-Migratory Effects in Human Neuroendocrine Tumour Cells in vitro
T2 - Evidence for ‘Off-Target' Effects not Mediated by c-Met Inhibition
AU - Reuther, Clemens
AU - Heinzle, Vera
AU - Spampatti, Matilde
AU - Vlotides, George
AU - de Toni, Enrico
AU - Spöttl, Gerald
AU - Maurer, Julian
AU - Nölting, Svenja
AU - Göke, Burkhard
AU - Auernhammer, Christoph J.
PY - 2015/8/25
Y1 - 2015/8/25
N2 - 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.
AB - 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.
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U2 - 10.1159/000439431
DO - 10.1159/000439431
M3 - Article
AN - SCOPUS:84940733443
JO - Neuroendocrinology
JF - Neuroendocrinology
SN - 0028-3835
ER -