Pyrvinium pamoate targets to multiple vulnerabilities of Merkel cell carcinoma

Among several WNT signaling perturbagens, we identified pyrvinium pamoate, an FDA-approved anthelminthic drug that exhibits anti-tumor abilities in multiple cancers. Through the integration of transcriptomic, network, and molecular analyses, we discovered that pyrvinium is broadly effective against Merkel cell carcinoma cell lines, and it targets multiple proposed MCC tumorigenesis pathways. Our study revealed that pyrvinium exerts anti-tumor activity in MCC not only through perturbing the canonical and non-canonical WNT signaling pathway but also non-specifically inhibiting cell growth - via the activation of the p53-mediated apoptosis pathway, modulation of mitochondrial function, and induction of endoplasmic reticulum (ER) stress. Overall design: Comparative gene expression profiling analysis of RNA-seq data for WaGa/MKL1 cell lines treated with DMSO and 1 µM pyrvinium pamoate for 6h and 24h

在多种WNT信号通路扰动剂中，本研究鉴定出帕莫酸吡维铵（pyrvinium pamoate）——一种经美国食品药品监督管理局（FDA）批准的抗蠕虫药物，其在多种癌症中均展现出抗肿瘤活性。通过整合转录组学、网络生物学与分子生物学分析手段，我们发现帕莫酸吡维铵对默克尔细胞癌（Merkel cell carcinoma, MCC）细胞系具有广谱抗肿瘤活性，且可靶向多条已被提出的默克尔细胞癌致癌通路。本研究表明，帕莫酸吡维铵在默克尔细胞癌中发挥抗肿瘤作用，不仅可干扰经典与非经典WNT信号通路，还可通过激活p53介导的细胞凋亡通路、调控线粒体功能以及诱导内质网（endoplasmic reticulum, ER）应激，非特异性抑制细胞增殖。实验整体设计：对经二甲基亚砜（dimethyl sulfoxide, DMSO）与1 μM帕莫酸吡维铵处理6小时、24小时的WaGa/MKL1细胞系的RNA测序（RNA-seq）数据开展比较基因表达谱分析。