Xu Jiabin, Koval Alexey, Katanaev Vladimir L
Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Front Oncol. 2020 Dec 10;10:602817. doi: 10.3389/fonc.2020.602817. eCollection 2020.
Wnt signaling plays key roles in oncogenic transformation and progression in a number of cancer types, including tumors in the breast, colon, ovaries, liver, and other tissues. Despite this importance, no therapy targeting the Wnt pathway currently exists. We have previously shown that the anti-mycobacterium drug clofazimine is a specific inhibitor of Wnt signaling and cell proliferation in triple-negative breast cancer (TNBC). Here, we expand the applicability of clofazimine to a set of other Wnt-dependent cancers. Using a panel of cell lines from hepatocellular carcinoma, glioblastoma, as well as colorectal and ovarian cancer, we show that the efficacy of clofazimine against a given cancer type correlates with the basal levels of Wnt pathway activation and the ability of the drug to inhibit Wnt signaling in it, being further influenced by the cancer mutational spectrum. Our study establishes the basis for patient stratification in the future clinical trials of clofazimine and may ultimately contribute to the establishment of the Wnt pathway-targeted therapy against a diverse set of cancer types relying on the oncogenic Wnt signaling.
Wnt信号通路在多种癌症类型（包括乳腺癌、结肠癌、卵巢癌、肝癌和其他组织中的肿瘤）的致癌转化和进展中发挥关键作用。尽管其具有重要性，但目前尚无针对Wnt通路的疗法。我们之前已经表明，抗分枝杆菌药物氯法齐明是三阴性乳腺癌（TNBC）中Wnt信号通路和细胞增殖的特异性抑制剂。在此，我们将氯法齐明的适用性扩展到一组其他依赖Wnt的癌症。使用来自肝细胞癌、胶质母细胞瘤以及结直肠癌和卵巢癌的一系列细胞系，我们表明氯法齐明对特定癌症类型的疗效与Wnt通路激活的基础水平以及该药物在其中抑制Wnt信号的能力相关，并进一步受到癌症突变谱的影响。我们的研究为氯法齐明未来临床试验中的患者分层奠定了基础，并最终可能有助于建立针对多种依赖致癌Wnt信号的癌症类型的Wnt通路靶向疗法。
