Unlike cutaneous melanoma, uveal melanoma (UM) is characterized by mutations in GNAQ and GNA11 and remains a fatal disease because there is essentially no effective targeted therapy or immunotherapy available. We report the discovery of the copper ionophore elesclomol as a GNAQ/11-specific UM inhibitor. Elesclomol was identified in a differential cytotoxicity screen of an in-house tool compound library, and its in vivo pharmacological efficacy was further confirmed in zebrafish and mouse UM models. Mechanistically, elesclomol transports copper to mitochondria and produces a large amount of reactive oxygen species (ROS) as Cu(II) is reduced to Cu(I) in GNAQ/11-mutant UM cells, which selectively activates LATS1 kinase in the Hippo signaling pathway and consequently promotes YAP phosphorylation and inhibits its nuclear accumulation. The inactivation of YAP downregulates the expression of SNAI2, which in turn suppresses the migration of UM cells. These findings were cross validated by our clinical observation that YAP activation was found specifically in UM samples with a GNAQ/11 mutation. Furthermore, addition of binimetinib, a MEK inhibitor, to elesclomol increased its synthetic lethality to GNAQ/11-mutant UM cells, thereby overriding drug resistance. This effect was confirmed in an orthotopic xenograft model and in a patient-derived xenograft model of UM. These studies reveal a novel mechanistic basis for repurposing elesclomol by showing that copper homeostasis is a GNAQ/11-specific vulnerability in UM. Elesclomol may provide a new therapeutic path for selectively targeting malignant GNAQ/11-mutant UM.

与皮肤黑色素瘤不同，葡萄膜黑色素瘤 (UM) 的特点是GNAQ和GNA11突变，并且仍然是一种致命的疾病，因为基本上没有有效的靶向治疗或免疫治疗。我们报告了铜离子载体艾司氯醇作为GNAQ/11特异性 UM 抑制剂的发现。 Elesclomol 在内部工具化合物库的差异细胞毒性筛选中得到鉴定，其体内药理学功效在斑马鱼和小鼠 UM 模型中得到进一步证实。从机制上讲，艾司氯醇将铜转运至线粒体，并在GNAQ/11突变 UM 细胞中将铜 (II) 还原为铜 (I) 时产生大量活性氧 (ROS)，选择性激活 Hippo 信号通路中的 LATS1 激酶从而促进 YAP 磷酸化并抑制其核积累。 YAP 失活会下调SNAI2的表达，从而抑制 UM 细胞的迁移。这些发现通过我们的临床观察进行了交叉验证，即在具有GNAQ/11突变的 UM 样本中特别发现了 YAP 激活。此外，在艾司洛莫中添加 MEK 抑制剂 binimetinib 增加了其对GNAQ / 11突变 UM 细胞的合成致死率，从而克服了耐药性。这种效应在 UM 的原位异种移植模型和患者来源的异种移植模型中得到证实。这些研究表明铜稳态是 UM 中GNAQ / 11特异性的脆弱性，从而揭示了重新利用艾司洛莫的新机制基础。艾来氯醇可能为选择性靶向恶性GNAQ / 11-突变体UM提供新的治疗途径。