Uveal melanoma (UM) is among the most common primary intraocular neoplasms in adults, with limited therapeutic options for advanced/metastatic disease. Since UM is characterized by infrequent p53 mutation coupled with the overexpression of MDM4, a major negative regulator of p53, we aimed to investigate in this study the effects on UM cells of CEP-1347, a novel MDM4 inhibitor with a known safety profile in humans. We also examined the impact of CEP-1347 on the protein kinase C (PKC) pathway, known to play a pivotal role in UM cell growth. High-grade UM cell lines were used to analyze the effects of genetic and pharmacological inhibition of MDM4 and PKC, respectively, as well as those of CEP-1347 treatment, on p53 expression and cell viability. The results showed that, at its clinically relevant concentrations, CEP-1347 reduced not only MDM4 expression but also PKC activity, activated the p53 pathway, and effectively inhibited the growth of UM cells. Importantly, whereas inhibition of either MDM4 expression or PKC activity alone failed to efficiently activate p53 and inhibit cell growth, inhibition of both resulted in effective activation of p53 and inhibition of cell growth. These data suggest that there exists a hitherto unrecognized interaction between MDM4 and PKC to inactivate the p53-dependent growth control in UM cells. CEP-1347, which dually targets MDM4 and PKC, could therefore be a promising therapeutic candidate in the treatment of UM.
葡萄膜黑色素瘤（UM）是成人中最常见的原发性眼内肿瘤之一，对于晚期/转移性疾病的治疗选择有限。鉴于UM具有p53突变罕见且MDM4（p53的主要负调控因子）过度表达的特征，本研究旨在探讨CEP-1347（一种已知在人体中具有安全性的新型MDM4抑制剂）对UM细胞的影响。同时，我们还研究了CEP-1347对蛋白激酶C（PKC）通路的作用，已知该通路在UM细胞生长中起关键作用。采用高级别UM细胞系，分别分析了遗传和药理学抑制MDM4与PKC，以及CEP-1347处理对p53表达和细胞活力的影响。结果显示，在临床相关浓度下，CEP-1347不仅能降低MDM4表达，还能抑制PKC活性，激活p53通路，并有效抑制UM细胞生长。重要的是，单独抑制MDM4表达或PKC活性均未能有效激活p53和抑制细胞生长，而同时抑制两者则能有效激活p53并抑制细胞生长。这些数据表明，MDM4与PKC之间存在一种迄今未被认识的相互作用，共同使UM细胞中依赖p53的生长调控失活。因此，双重靶向MDM4和PKC的CEP-1347可能成为治疗UM的有前景的候选药物。
CEP-1347 Dually Targets MDM4 and PKC to Activate p53 and Inhibit the Growth of Uveal Melanoma Cells
肿瘤(癌症)患者之家