Biophenics Laboratory, Translational Research Department, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, 26, rue d'Ulm, 75005 Paris, France.
Mol Oncol. 2014 Dec;8(8):1508-20. doi: 10.1016/j.molonc.2014.06.004. Epub 2014 Jun 13.
Uveal melanoma (UM) is the most common primary tumor of the eye in adults. There is no standard adjuvant treatment to prevent metastasis and no effective therapy in the metastatic setting. We have established a unique panel of 7 UM cell lines from either patient's tumors or patient-derived tumor xenografts (PDXs). This panel recapitulates the molecular landscape of the disease in terms of genetic alterations and mutations. All the cell lines display GNAQ or GNA11 activating mutations, and importantly four of them display BAP1 (BRCA1 associated protein-1) deficiency, a hallmark of aggressive disease. The mTOR pathway was shown to be activated in most of the cell lines independent of AKT signaling. mTOR inhibitor Everolimus reduced the viability of UM cell lines and significantly delayed tumor growth in 4 PDXs. Our data suggest that mTOR inhibition with Everolimus, possibly in combination with other agents, may be considered as a therapeutic option for the management of uveal melanoma.
葡萄膜黑色素瘤（UM）是成年人眼部最常见的原发性肿瘤。目前尚无预防转移的标准辅助治疗方法，转移性疾病也没有有效的治疗方法。我们从患者的肿瘤或患者来源的肿瘤异种移植物（PDX）中建立了一个独特的 7 个 UM 细胞系的面板。该面板在遗传改变和突变方面重现了疾病的分子特征。所有细胞系均显示 GNAQ 或 GNA11 激活突变，重要的是其中 4 个显示 BAP1（BRCA1 相关蛋白-1）缺陷，这是侵袭性疾病的标志。mTOR 途径在大多数细胞系中被激活，而与 AKT 信号无关。mTOR 抑制剂依维莫司降低了 UM 细胞系的活力，并显著延迟了 4 个 PDX 中的肿瘤生长。我们的数据表明，依维莫司抑制 mTOR，可能与其他药物联合使用，可被视为管理葡萄膜黑色素瘤的一种治疗选择。
