Saracatinib impairs the peritoneal dissemination of diffuse‐type gastric carcinoma cells resistant to Met and fibroblast growth factor receptor inhibitors

Cancer Science

Hideki Yamaguchi²  Miho Takanashi²  Nachi Yoshida²  Yuumi Ito²  Reiko Kamata²  Kiyoko Fukami³  Kazuyoshi Yanagihara¹ 

[1] Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan;Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan;Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan

关键词: c‐Met;    c‐src;    neoplasm metastasis;    saracatinib;    stomach neoplasms;   

DOI  :  10.1111/cas.12387

来源: Wiley

【 摘 要 】

Abstract

Diffuse-type gastric carcinomas (DGC) exhibit more aggressive progression and poorer prognosis than intestinal-type and other gastric carcinomas. To identify potential therapeutic targets, we examined protein tyrosine phosphorylation in a panel of DGC and other gastric cancer cell lines. Protein tyrosine phosphorylation was significantly enhanced or altered in DGC cell lines compared with that in other gastric cancer cell lines. Affinity purification and mass spectrometry analysis of tyrosine-phosphorylated proteins identified Met as a protein that is preferentially expressed and phosphorylated in DGC cell lines. Unexpectedly, Met inhibitors blocked cell growth, Met downstream signaling and peritoneal dissemination in vivo in only a subset of cell lines that exhibited remarkable overexpression of Met. Likewise, only cell lines with overexpression of fibroblast growth factor receptor 2 (FGFR2) or phosphorylation of FRS2 were sensitive to an FGFR2 inhibitor. 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. 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.

【 授权许可】

CC BY-NC-ND   
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.