Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea.
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Int J Mol Sci. 2024 May 29;25(11):5975. doi: 10.3390/ijms25115975.
Capmatinib and savolitinib, selective inhibitors, are widely used to treat various -positive cancers. In this study, we aimed to determine the effects of these inhibitors on -amplified gastric cancer (GC) cells. Methods: After screening 37 GC cell lines, the following cell lines were found to be -positive with copy number variation >10: SNU-620, ESO51, MKN-45, SNU-5, and OE33 cell lines. Next, we assessed the cytotoxic response of these cell lines to capmatinib or savolitinib alone using cell counting kit-8 and clonogenic cell survival assays. Western blotting was performed to assess the effects of capmatinib and savolitinib on the signaling pathway. Xenograft studies were performed to evaluate the in vivo therapeutic efficacy of savolitinib in MKN-45 cells. Savolitinib and capmatinib exerted anti-proliferative effects on MET-amplified GC cell lines in a dose-dependent manner. Savolitinib inhibited the phosphorylation of and downstream signaling pathways, such as the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways, in -amplified GC cells. Additionally, savolitinib significantly decreased the number of colonies formed on the soft agar and exerted dose-dependent anti-tumor effects in an MKN-45 GC cell xenograft model. Furthermore, a combination of trastuzumab and capmatinib exhibited enhanced inhibition of AKT and ERK activation in human epidermal growth factor receptor-2 ()- and -positive OE33 cells. Targeting MET with savolitinib and capmatinib efficiently suppressed the growth of -amplified GC cells. Moreover, these MET inhibitors exerted synergistic effects with trastuzumab on - and -amplified GC cells.
卡马替尼和索凡替尼是两种选择性抑制剂，广泛用于治疗各种 MET 阳性癌症。在本研究中，我们旨在确定这些抑制剂对 MET 扩增型胃癌（GC）细胞的影响。
在筛选了 37 种 GC 细胞系后，我们发现以下细胞系存在 MET 阳性，拷贝数变异 >10：SNU-620、ESO51、MKN-45、SNU-5 和 OE33 细胞系。接下来，我们使用细胞计数试剂盒-8 和集落形成细胞存活测定法评估这些细胞系对卡马替尼或索凡替尼单独治疗的细胞毒性反应。Western blot 用于评估卡马替尼和索凡替尼对 MET 信号通路的影响。进行异种移植研究以评估索凡替尼在 MKN-45 细胞中的体内治疗疗效。
卡马替尼和索凡替尼以剂量依赖性方式对 MET 扩增型 GC 细胞系发挥抗增殖作用。索凡替尼抑制 MET 扩增型 GC 细胞中磷酸化和下游信号通路，如蛋白激酶 B（AKT）和细胞外信号调节激酶（ERK）通路。此外，索凡替尼显著减少软琼脂上形成的菌落数量，并在 MKN-45 GC 细胞异种移植模型中发挥剂量依赖性抗肿瘤作用。此外，曲妥珠单抗与卡马替尼联合使用可增强人表皮生长因子受体 2（HER2）阳性 OE33 细胞中 AKT 和 ERK 激活的抑制作用。用索凡替尼和卡马替尼靶向 MET 可有效抑制 MET 扩增型 GC 细胞的生长。此外，这些 MET 抑制剂与曲妥珠单抗在 HER2-和 MET-扩增型 GC 细胞中发挥协同作用。
