title: Saracatinib impairs the peritoneal dissemination of diffuse-type gastric carcinoma cells resistant to Met and fibroblast growth factor receptor inhibitors.
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.
authors.affiliation: Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Miho
authors.initials: M
authors.lastname: Takanashi
authors.forename: Nachi
authors.initials: N
authors.lastname: Yoshida
authors.forename: Yuumi
authors.initials: Y
authors.lastname: Ito
authors.forename: Reiko
authors.initials: R
authors.lastname: Kamata
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Fukami
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Sakai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D058990:Molecular Targeted Therapy; D010537:Peritoneum / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C515233:saracatinib; C496353:FGFR2 protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051497:Receptor, Fibroblast Growth Factor, Type 2; D019061:src-Family Kinases
keywords: c-Met; c-src; neoplasm metastasis; saracatinib; stomach neoplasms