DataSheet_1_Beyond TNBC: Repositioning of Clofazimine Against a Broad Range of Wnt-Dependent Cancers.docx

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（Wnt signaling）在包括乳腺、结肠、卵巢、肝脏及其他组织肿瘤在内的多种癌症类型的致癌转化与进展过程中发挥关键作用。尽管其重要性不言而喻，但目前尚无靶向Wnt通路的治疗药物。本团队既往研究表明，抗分枝杆菌药物氯法齐明（clofazimine）是三阴性乳腺癌（triple-negative breast cancer, TNBC）中Wnt信号通路与细胞增殖的特异性抑制剂。本研究将氯法齐明的应用范围拓展至其他依赖Wnt信号通路的癌症类型。我们采用一组源自肝细胞癌、胶质母细胞瘤、结直肠癌及卵巢癌的细胞系panel，结果显示氯法齐明对特定癌症类型的疗效，与该癌症的Wnt通路基础激活水平及药物抑制其Wnt信号通路的能力呈正相关，且其疗效进一步受癌症突变谱的影响。本研究为未来氯法齐明临床试验中的患者分层提供了理论基础，并有望最终推动针对依赖致癌性Wnt信号通路的多种癌症类型的Wnt通路靶向治疗方案的确立。