Zaman Shadia, Shentu Shujun, Yang Jing, He Jin, Orlowski Robert Z, Stellrecht Christine M, Gandhi Varsha
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Neoplasia. 2015 Mar;17(3):289-300. doi: 10.1016/j.neo.2015.01.006.
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.
肝细胞生长因子（HGF）/MNNG HOS转化基因（MET）通路调节细胞生长、存活和迁移。MET在多种恶性肿瘤中发生突变或扩增。在骨髓瘤中，MET未发生突变，但患者血浆中HGF浓度高、MET表达水平和基因拷贝数高，这些与预后不良和疾病进展相关。我们之前的研究表明，MET对骨髓瘤细胞存活至关重要，敲低它可诱导细胞凋亡。在我们当前的研究中，我们测试了小分子MET药理抑制剂替凡替尼（ARQ 197）。在临床可达到的浓度下，替凡替尼在所有12种测试的人骨髓瘤细胞系中诱导凋亡率>50%。这种生物学反应与MET信号下调以及丝裂原活化蛋白激酶和磷脂酰肌醇3激酶通路的抑制有关，这两条通路是HGF/MET轴的下游通路。替凡替尼在诱导对标准化疗（美法仑、地塞米松、硼替佐米和来那度胺）耐药的骨髓瘤细胞系凋亡方面同样有效，在与保护性骨髓微环境或外源性细胞因子共培养的细胞中也同样有效。替凡替尼诱导患者CD138 +浆细胞凋亡，并在骨髓瘤异种移植小鼠模型中显示出疗效。基于这些数据，我们启动了一项针对复发/难治性多发性骨髓瘤（MM）的临床试验。总之，MET抑制剂可能是一种有吸引力的基于靶点的MM治疗策略。
