Division of Internal Medicine, National Army Capital Hospital, The Armed Forces Medical Command, Sungnam, 13574, Republic of Korea.
Hallym Translational Research Institute, Hallym University College of Medicine, Anyang-si, Gyeonggi-do, 14068, Republic of Korea.
Invest New Drugs. 2020 Dec;38(6):1633-1640. doi: 10.1007/s10637-020-00940-3. Epub 2020 May 2.
Tivantinib has been described as a selective inhibitor of c-Met and is being studied in various types of cancer. In this study, we evaluated the effects of tivantinib on the suppression of gastric cancer (GC) cell migration and apoptosis. We also examined the mechanism of action of tivantinib by oncogenic pathway analysis. We applied an RNA-sequencing approach in 34 GC patients to identify oncogenes that are differentially expressed in GC tissues. To examine the inhibitory effect of tivantinib on GC cells, we conducted apoptosis analysis using an annexin V-APC/PI apoptosis detection kit and trans-well migration assay with human GC cell lines. For oncogenic pathway analysis, Western blot and quantitative real-time PCR analysis were used to detect the expression of proteins and genes before and after tivantinib exposure. In the RNA-sequencing analysis of 34 GC patients, c-Met and VEGFA genes were expressed and positively correlated with each other. Cell migration and apoptosis analysis demonstrated that tivantinib induced the best inhibition effect in SNU620, MKN45 (carries VEGFB mutation), AGS, and MKN28 cells, but not in KATO III (carries VEGFB and VEGFC mutations) cells. Oncogenic pathway analysis showed that tivantinib, in addition to c-Met signaling pathway inhibition, also inhibits VEGF signaling and MYC expression in VEGFA-expressing GC cells. We found that tivantinib has anti-cancer activity not only in GC cells overexpressing c-Met but also in non-c-Met GC cells by inhibition of the VEGF signaling pathway.
替沃扎尼被描述为一种 c-Met 的选择性抑制剂，目前正在多种类型的癌症中进行研究。在这项研究中，我们评估了替沃扎尼对抑制胃癌（GC）细胞迁移和凋亡的作用。我们还通过致癌途径分析来研究替沃扎尼的作用机制。我们对 34 名 GC 患者进行了 RNA 测序，以鉴定在 GC 组织中差异表达的致癌基因。为了研究替沃扎尼对 GC 细胞的抑制作用，我们使用膜联蛋白 V-APC/PI 凋亡检测试剂盒和人 GC 细胞系的 Transwell 迁移实验进行了凋亡分析。为了进行致癌途径分析，我们使用 Western blot 和定量实时 PCR 分析检测了替沃扎尼暴露前后蛋白质和基因的表达。在对 34 名 GC 患者的 RNA 测序分析中，c-Met 和 VEGFA 基因表达并相互正相关。细胞迁移和凋亡分析表明，替沃扎尼在 SNU620、MKN45（携带 VEGFB 突变）、AGS 和 MKN28 细胞中诱导的抑制效果最佳，但在 KATO III（携带 VEGFB 和 VEGFC 突变）细胞中无此效果。致癌途径分析表明，替沃扎尼除了抑制 c-Met 信号通路外，还抑制了 VEGFA 表达的 GC 细胞中的 VEGF 信号和 MYC 表达。我们发现，替沃扎尼通过抑制 VEGF 信号通路，不仅在过表达 c-Met 的 GC 细胞中具有抗癌活性，而且在非 c-Met GC 细胞中也具有抗癌活性。
