Saracatinib impairs the peritoneal dissemination of diffuse-type gastric carcinoma cells resistant to Met and fibroblast growth factor receptor inhibitors.
Bottom Line: A Src inhibitor saracatinib impaired growth in cell lines that are insensitive to both Met and FGFR2 inhibitors.Saracatinib also effectively impaired peritoneal dissemination of Met-independent and FGFR2-independent SGC cells.Moreover, DGC cell lines exhibited nearly mutually exclusive susceptibility to Met, FGFR and Src inhibitors.
Affiliation: Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.Show MeSH
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Mentions: The IC50 values of Met inhibitors in 44As3 and 58As9 cells were approximately 1500 and 19 nM for PHA-665752, >10 000 and 6.9 nM for JNJ-38877605, and 2600 and 21 nM for PF-2341066, respectively (Fig. S2a). Met inhibitors significantly blocked phosphorylation of Met in both 44As3 and 58As9 cells (Fig.2a). Nonetheless, overall protein tyrosine phosphorylation and phosphorylation of ERK, Akt and Stat3 were significantly decreased only in 58As9 cells (Fig.2a,b). Interestingly, Src phosphorylation was rather increased in 58As9 cells upon Met inhibition, whereas it was unchanged in 44As3 cells (Fig.2a). Similar results were obtained with PF-2341066 (Fig. S2b). Met inhibitor treatment also induced marked changes in cell morphology in 58As9 but not in 44As3 cells: rounded morphology was converted to flattened and adherent phenotypes (Fig.2c). Serum starvation reduced and following HGF stimulation increased Met phosphorylation in 44As3 cells, whereas Met was constitutively phosphorylated in 58As9 cells (Fig.2d). Consequently, growth of 44As3 but not of 58As9 cells was sensitive to serum starvation (Fig.2e). These results indicate that overexpressed Met proteins confer the capability for serum-independent growth to 58As9 cells via activation of downstream signaling pathways, and, therefore, that 58As9 cells are susceptible to Met inhibitors.
Affiliation: Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.