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首页> 外文期刊>Neoplasia: an international journal for oncology research >Targeting the Pro-Survival Protein MET with Tivantinib (ARQ 197) Inhibits Growth of Multiple Myeloma Cells
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Targeting the Pro-Survival Protein MET with Tivantinib (ARQ 197) Inhibits Growth of Multiple Myeloma Cells

机译：靶向Pro-survival蛋白与Tivantinib（ARQ 197）相遇，抑制多发性骨髓瘤细胞的生长

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The hepatocyte growth factor (HGF)/MNNG HOS transforming gene (MET) pathway regulates cell growth, survival, and migration. MET is mutated or amplified in several malignancies. In myeloma, MET is not mutated, but patients have high plasma concentrations of HGF, high levels of MET expression, and gene copy number, which are associated with poor prognosis and advanced disease. Our previous studies demonstrated that MET is critical for myeloma cell survival and its knockdown induces apoptosis. In our current study, we tested tivantinib (ARQ 197), a small-molecule pharmacological MET inhibitor. At clinically achievable concentrations, tivantinib induced apoptosis by &50% in all 12 human myeloma cell lines tested. This biologic response was associated with down-regulation of MET signaling and inhibition of the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, which are downstream of the HGF/MET axis. Tivantinib was equally effective in inducing apoptosis in myeloma cell lines resistant to standard chemotherapy (melphalan, dexamethasone, bortezomib, and lenalidomide) as well as in cells that were co-cultured with a protective bone marrow microenvironment or with exogenous cytokines. Tivantinib induced apoptosis in CD138+ plasma cells from patients and demonstrated efficacy in a myeloma xenograft mouse model. On the basis of these data, we initiated a clinical trial for relapsed/refractory multiple myeloma (MM). In conclusion, MET inhibitors may be an attractive target-based strategy for the treatment of MM.
机译：肝细胞生长因子（HGF）/ MNNG HOS转化基因（MET）途径调节细胞生长，生存和迁移。在几个恶性肿瘤中均匀突变或扩增。在骨髓瘤中，遇见没有突变，但患者具有高血浆浓度的HGF，高水平的表达，以及基因拷贝数，与预后差和晚期疾病有关。我们以前的研究表明，满足对骨髓瘤细胞生存至关重要，其敲低诱导细胞凋亡。在我们目前的研究中，我们测试了一个小分子药理Met抑制剂的Tivantinib（ARQ 197）。在临床上可实现的浓度下，Tivantinib在所有12个人骨髓瘤细胞系中诱导细胞凋亡。50％测试。该生物响应与达到偶极活化的蛋白激酶和磷酸亚膦酸磷酸亚磷酶3-激酶途径的达到信号传导和抑制的下调有关，其在HGF / MET轴的下游。 Tivantinib同样有效地诱导骨髓瘤细胞凋亡，抗标准化疗（Melphalan，Dexamethasone，Bortezomib和Lenalidomide）以及用保护性骨髓微环境或外源细胞因子共同培养的细胞中。 Tivantinib诱导来自患者的CD138 +血浆细胞的细胞凋亡，并在骨髓瘤异种移植小鼠模型中证明了疗效。在这些数据的基础上，我们启动了复发/难治多骨髓瘤（mm）的临床试验。总之，Met抑制剂可能是一种有吸引力的基于目标的摩擦策略。

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