Effect of tivantinib on VEGF signaling pathways and apoptosis of gastric cancer cells with c-MET or VEGFA amplification.

Abstract

e14719 Background: VEGFA is the key mediator of angiogenesis in cancer and previous studies reported that VEGFA expression was significantly up-regulated in gastric cancer tissues compared with matched normal tissues. We showed that increased levels of VEGFA are significantly associated with expression of hepatocyte growth factor receptor (MET) (r = 0.6255, P < 0.0001). In addition, it is well known that c-MET is potentially a highly plausible target for cancer therapy in gastric cancer. In this study, cytotoxic activity of tivantinib were evaluated in gastric cancer cells with high c-MET expression or VEGFA amplification. Methods: In this study, Western blot and quantitative real-time PCR analysis were used to detect the expression of protein and genes after treatment of tivantinib. In addition, MTS, flow cytometry, and migration assay were used. Results: Tivantinib inhibited growths of a high c-MET-expressed or VEGFA-amplified cell lines. Furthermore, in migration and apoptosis analysis, tivantinib induced apoptosis of SNU620, MKN45 (carried VEGFB mutation), AGS, and MKN28 cells but not in KATO III (carried VEGFB and VEGFC mutation) cells. We also found that tivantinib inhibited the VEGF signaling pathway and MYC expression in VEGFA-amplified gastric cancer cell lines. Conclusions: The data indicate that tivantinib could be a potential therapeutic agent for the treatment of gastric cancer with high c-MET expression or VEGFA amplification.