Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
Int J Cancer. 2018 Jul 1;143(1):151-159. doi: 10.1002/ijc.31304. Epub 2018 Feb 23.
Receptor tyrosine kinase MET (c-MET) has received considerable attention as a potential target for gastric cancer (GC) therapy and a number of c-MET inhibitors have been developed. For successful drug development, proper preclinical studies especially using patient derived cancer cell lines are very important. We profiled MET and MET-related characteristics in 49 GC cell lines to utilize them as models in preclinical studies of GC. Forty-nine cell lines were analyzed for genetic, biological, and molecular status to characterize MET and MET-related molecules. Four c-MET inhibitors were tested to elucidate the dependency on MET pathway in the 49 GC cell lines. Six of 49 cell lines were MET amplified with overexpression of c-MET and p-MET. The variants of MET were not associated with c-MET expression or amplification. Hs746T showed an exon 14 deletion in conjunction with MET amplification. The cell lines were divided into 6 MET amplified, 2 c-MET overexpressed, 2 hepatocyte growth factor (HGF) overexpressed, and 39 MET-negative subgroups. Except tivantinib, the c-MET inhibitors showed higher inhibition (%) in MET amplified than in MET nonamplified cell lines that MET amplified cell lines showed MET pathway dependency. However, the c-MET overexpressed and HGF overexpressed cell lines showed moderate dependency on MET pathway. Well-characterized cell lines are very important in studying drug development. Our 49 GC cell lines had various characteristics of MET and MET-related molecules and MET pathway dependency. These provide a promising platform for development of various RTK inhibitors including c-MET inhibitors.
受体酪氨酸激酶 MET（c-MET）作为胃癌（GC）治疗的潜在靶点受到了相当多的关注，并且已经开发出了许多 c-MET 抑制剂。为了成功开发药物，适当的临床前研究，特别是使用患者来源的癌细胞系进行研究非常重要。我们对 49 种 GC 细胞系中的 MET 和 MET 相关特征进行了分析，以便将其用作 GC 临床前研究的模型。对 49 种细胞系进行了基因、生物学和分子状态分析，以对 MET 和 MET 相关分子进行特征分析。测试了 4 种 c-MET 抑制剂，以阐明它们在 49 种 GC 细胞系中对 MET 通路的依赖性。在 49 种细胞系中，有 6 种细胞系发生了 MET 扩增，伴有 c-MET 和 p-MET 的过表达。MET 的变体与 c-MET 的表达或扩增无关。Hs746T 显示与 MET 扩增一起发生的外显子 14 缺失。细胞系被分为 6 个 MET 扩增、2 个 c-MET 过表达、2 个肝细胞生长因子（HGF）过表达和 39 个 MET 阴性亚组。除了替沃扎尼之外，c-MET 抑制剂在 MET 扩增细胞系中的抑制率（%）高于在 MET 非扩增细胞系中的抑制率，表明 MET 扩增细胞系对 MET 通路有依赖性。然而，c-MET 过表达和 HGF 过表达的细胞系对 MET 通路有中等程度的依赖性。特征明确的细胞系在研究药物开发中非常重要。我们的 49 种 GC 细胞系具有不同的 MET 和 MET 相关分子特征以及 MET 通路依赖性。这些为开发各种 RTK 抑制剂，包括 c-MET 抑制剂，提供了一个有前途的平台。
