14070 Background: Scirrhous gastric carcinoma, a diffusely infiltrating also known as linitis plastica-type carcinoma, carries the highest mortality of all gastric cancers. Scirrhous carcinoma cells with amplification of the activated K-samII gene, which encodes fibroblast growth factor receptor type 2 (FGF-R2), have a growth advantage during tumor progression The poor prognosis carried by scirrhous gastric cancer is closely associated with amplification of the K-samII/FGF-R2, a tyrosine kinase growth factor receptor. Ki23057, a newly developed small molecule acting K-samII/FGF-R2 inhibitor, is a kinase inhibitor that competes with ATP for the binding site in the kinase, thus strongly blocking phosphorylation of FGF-R2. The aim of the current study is to clarify the possibility of molecular target therapy with Ki23057 for treating scirrhous gastric cancer. Methods: Five human gastric cancer cell lines were used. OCUM-2MD3 and OCUM-8 were derived from scirrhous carcinomas. MKN-7, MKN-45 and MKN-74 cells were derived from non-scirrhous carcinomas. In vitro effects of Ki23057 on cell growth were determined by calculating the number of cancer cells. The influences of Ki23057 on the MAP kinase and PI3 kinase signaling pathways and the apoptosis pathway in the gastric cancer cells were also examined. For in vivo experiments, the Ki23057 was administered orally to mouse models of peritoneal dissemination. Results: K-samII amplification was found in OCUM-2MD3 and OCUM-8 cells, but not in MKN-7, MKN-45, or MKN-74 cells. Ki23057 significantly inhibited the proliferation of scirrhous cancer cells, but not non- scirrhous gastric carcinoma cells. Ki23057 decreased phosphorylation of K-samII/FGF-R2, ERK and Akt, and increased apoptosis in scirrhous cancer lines. The oral Ki23057 administration significantly (p<0.001) prolonged survival of mice with peritoneal dissemination following injection of OCUM-2MD3 scirrhous cancer cells. Conclusions: A novel K-samII/FGF-R2 phosphorylation inhibitor, Ki23057, appears therapeutically promising in scirrhous gastric carcinoma with K-samII amplification. No significant financial relationships to disclose.
Multidisciplinary therapy for scirrhous gastric cancer: a retrospective analysis and proposal of new treatment strategy
