Response of Merkel Cell Polyomavirus-Positive Merkel Cell Carcinoma Xenografts to a Survivin Inhibitor

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer associated with high mortality. Merkel cell polyomavirus (MCV), discovered in 2008, is associated with ~80% of MCC. The MCV large tumor (LT) oncoprotein upregulates the cellular oncoprotein survivin through its conserved retinoblastoma protein-binding motif. We confirm here that YM155, a survivin suppressor, is cytotoxic to MCV-positive MCC cells in vitro at nanomolar levels. Mouse survival was significantly improved for NOD-Scid-Gamma mice treated with YM155 in a dose and duration dependent manner for 3 of 4 MCV-positive MCC xenografts. One MCV-positive MCC xenograft (MS-1) failed to significantly respond to YM155, which corresponds with in vitro dose-response activity. Combination treatment of YM155 with other chemotherapeutics resulted in additive but not synergistic cell killing of MCC cell lines in vitro. These results suggest that survivin targeting is a promising therapeutic approach for most but not all MCV-positive MCCs.

默克尔细胞癌（Merkel cell carcinoma, MCC）是一种致死率较高的神经内分泌皮肤恶性肿瘤。2008年发现的默克尔细胞多瘤病毒（Merkel cell polyomavirus, MCV）与约80%的MCC病例相关。MCV大T（large tumor, LT）癌蛋白可通过其保守的视网膜母细胞瘤蛋白结合基序，上调细胞癌蛋白生存素（survivin）的表达。本研究证实，生存素抑制剂YM155在体外可在纳摩尔浓度下对MCV阳性的MCC细胞产生细胞毒性。在4株MCV阳性MCC异种移植瘤模型中，经YM155按剂量和给药时长依赖性方案治疗后，其中3株对应的宿主NOD-Scid-Gamma小鼠的生存期得到显著延长。其中1株MCV阳性MCC异种移植瘤（MS-1）未对YM155产生显著应答，该结果与其体外剂量反应活性相一致。将YM155与其他化疗药物联合使用时，在体外可对MCC细胞系产生相加而非协同的杀伤效果。上述结果表明，靶向生存素可为多数（而非全部）MCV阳性MCC患者提供极具潜力的治疗策略。