Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
JCI Insight. 2022 Jul 8;7(13):e160513. doi: 10.1172/jci.insight.160513.
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin with 2 etiologies. Merkel cell polyomavirus (MCPyV) integration is present in about 80% of all MCC. Virus-positive MCC (MCCP) tumors have few somatic mutations and usually express WT p53 (TP53). By contrast, virus-negative MCC (MCCN) tumors present with a high tumor mutational burden and predominantly UV mutational signature. MCCN tumors typically contain mutated TP53. MCCP tumors express 2 viral proteins: MCPyV small T antigen and a truncated form of large T antigen. MCPyV ST specifically activates expression of MDM2, an E3 ubiquitin ligase of p53, to inhibit p53-mediated tumor suppression. In this study, we assessed the efficacy of milademetan, a potent, selective, and orally available MDM2 inhibitor in several MCC models. Milademetan reduced cell viability of WT p53 MCC cell lines and triggered a rapid and sustained p53 response. Milademetan showed a dose-dependent inhibition of tumor growth in MKL-1 xenograft and patient-derived xenograft models. Here, along with preclinical data for the efficacy of milademetan in WT p53 MCC tumors, we report several in vitro and in vivo models useful for future MCC studies.
默克尔细胞癌（Merkel cell carcinoma，MCC）是一种侵袭性的皮肤神经内分泌癌，有 2 种病因。约 80%的 MCC 存在 Merkel 细胞多瘤病毒（Merkel cell polyomavirus，MCPyV）整合。病毒阳性的 MCC（MCCP）肿瘤体细胞突变较少，通常表达 WT p53（TP53）。相比之下，病毒阴性的 MCC（MCCN）肿瘤具有较高的肿瘤突变负担和主要的 UV 突变特征。MCCN 肿瘤通常含有突变的 TP53。MCCP 肿瘤表达 2 种病毒蛋白：MCPyV 小 T 抗原和大 T 抗原的截断形式。MCPyV ST 特异性激活 MDM2 的表达，MDM2 是 p53 的 E3 泛素连接酶，以抑制 p53 介导的肿瘤抑制。在这项研究中，我们评估了米达美坦（一种有效的、选择性的、口服可用的 MDM2 抑制剂）在几种 MCC 模型中的疗效。米达美坦降低了 WT p53 MCC 细胞系的细胞活力，并引发了快速和持续的 p53 反应。米达美坦在 MKL-1 异种移植和患者来源的异种移植模型中表现出剂量依赖性的肿瘤生长抑制作用。在此，我们报告了几种体外和体内模型，除了 WT p53 MCC 肿瘤米达美坦疗效的临床前数据外，这些模型可用于未来的 MCC 研究。
