Saracatinib impairs the peritoneal dissemination of diffuse-type gastric carcinoma cells resistant to Met and fibroblast growth factor receptor inhibitors.
Bottom Line: 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.These results suggest that DGC have distinct sensitivities to molecular target drugs and that targeting Src is beneficial in the treatment of DGC insensitive to Met and FGFR inhibition.
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 saracatinib for the cell growth of 44As3 and 58As9 cells were 8.2 and 30 μM, respectively (Fig.4a). Saracatinib treatment significantly decreased overall protein tyrosine phosphorylation in 44As3 but not in 58As9 cells (Fig.4b). Interestingly, saracatinib did not affect the phosphorylation of Met, ERK and Akt (Fig.4c). Saracatinib administration reduced the incidence of ascites formation and tumor dissemination to diaphragm and liver in 44As3 cells expressing luciferase (44As3Luc; Table2). Although the incidence of dissemination to mesentery was not affected much by saracatinib, a marked reduction in the number of mesentery nodules was observed (Fig.4d,e). In vivo imaging analysis confirmed that saracatinib treatment significantly reduces the growth and dissemination of 44As3Luc cells (Fig.4f,g). In contrast, neither the incidence of omental metastasis nor the growth of omental tumors was affected by saracatinib treatment (Table2 and Fig.4h). Although saracatinib tended to suppress the formation of ascites and peritoneal dissemination by 58As9 cells, the effects were more moderate (Table2 and Fig.4d,e). These data indicate that saracatinib can suppress peritoneal dissemination of SGC cells that are insensitive to Met and FGFR inhibitors.
Affiliation: Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.