Synergistic antitumor effects of FGFR2 inhibitor with 5‐fluorouracil on scirrhous gastric carcinoma

Abstract

Scirrhous gastric carcinoma (SGC) carries the highest mortality because of a frequent metastasis to lymph node (LN). S1, a 5-fluorouracil (5-FU) analog, is clinically available for gastric cancer at an advanced stage. Fibroblast growth factor receptor 2 (FGFR2) is required for the proliferation of SGC. The objective of this study is to clarify the benefit of a combination of S1 and kinase inhibitors including FGFR2 inhibitor Ki23057 in gastric cancer. OCUM-2MLN and KATO-III were derived from SGC. MKN-7 and MKN-74 were derived from non-SGC. MTT assay was used to examine the growth-inhibitory activity of 5 small-synthetic molecules including Ki23057, Sunitinib, Glivec, Lapatinib or SU11274, in cells cultured with 5-FU. Combination effects of 5-FU with Ki23057 on proliferation, apoptosis and mRNA expression were examined. S1 and/or Ki23057 were administered to murine models of SGC created by the orthotopic inoculation of OCUM-2MLN cells. Ki23057 at 100 nM significantly (p < 0.01) inhibited the proliferation and decreased the phosphorylation of FGFR2 in SGC cells, but not in non-SGC. Ki23057 showed synergistic antitumor effects for SGC cells in combination with 5-FU using CalcuSyn analysis, but Sunitinib, Glivec, Lapatinib and SU11274 did not. The combination of Ki23057 and 5-FU decreased DPD expression and increased apoptosis rates and p21 expression level of SGC cells. The combined administration of S1 and Ki23057 significantly (p < 0.05) decreased orthotopic tumors as well as LN metastasis more effectively than S1 alone. These findings suggested that the combined treatment with 5-FU and Ki23057 produced synergistic antitumor effects and is therapeutically promising for SGC treatment.The characteristic clinical features of scirrhous gastric carcinoma (SGC), a diffusely infiltrating type of gastric carcinomas also known as linitis plastica-type gastric carcinoma, include rapidly progressive growth and a high frequency of metastasis to the lymph node (LN).1-3 SGC carries a worse prognosis among other types of gastric carcinomas, with 5-year survival rates in the range of 10-15%. 4,5 Chemotherapy is frequently recommended treatment for LN metastasis of gastric cancer in Japan. 6-9 A novel chemotherapeutic agent S1, a 5-fluorouracil (5-FU) analog, has recently become first-line chemotherapy for gastric cancer patients with LN metastasis. 9 Even so, however, the median survival duration in patients with advanced SGC continues to be less than a year. 6,7 Fibroblast growth factor receptor 2 (FGFR2) overexpression has been reported in about 40% of advanced stomach cancer cases and is especially frequent in SGC.10,11 FGFR2 is a member of the FGFR receptor tyrosine kinase (RTK) family, which consists of 4 receptors and 23 ligands. 12 The signal through FGFR2 and FGF7 is important for the growth of SGC with an amplification of the activated FGFR2 gene (KsamII). 1,10,11,13 Ki23057, a newly developed FGFR2 inhibitor, competes with ATP for the binding site in the kinase and therefore blocks the autophosphorylation of FGFR2 as p...

Genomic and epigenetic profiles of gastric cancer: Potential diagnostic and therapeutic applications

“…23 Moreover Ki23057 showed synergistic antitumor effects for SGC cells in combination with 5-FU using CalcuSyn analysis, and the combined administration of S1 and Ki23057 significantly decreased the growth of orthotopic tumors as well as lymph node metastasis more effectively than S1 alone. 23 These fi ndings suggest that targeting the FGFR2 gene produces potent antitumor effects and, if combined with chemotherapy, can produce synergistic effects. Thus, targeting FGFR2 is a promising strategy for SGC treatment (Fig.…”

Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application

“…Early development of FGFR inhibitors exhibits antitumor activity and present very specific toxicity profiles. Prior studies also indicate that FGFR inhibitors enhance tumor sensitivity to conventional anticancer drugs such as 5-fluorouracil, irinotecan, paclitaxel, and etoposide in human cancer cells acquiring anti-apoptotic potential based on aberrant FGFR activation [71, 72]. …”

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

“…The oral administration of Ki23057 prolongs the survival of mice with peritoneal metastasis of scirrhous cancer. The combined administration of S1 and Ki23057 decreases orthotopic tumors as well as LN metastasis more effectively than S1 alone [78,79]. FGFR-2 phosphorylation inhibitor appears therapeutically promising in scirrhous gastric carcinoma with K-samII amplification.…”