Madan Babita, Virshup David M
Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
Mol Cancer Ther. 2015 May;14(5):1087-94. doi: 10.1158/1535-7163.MCT-14-1038. Epub 2015 Apr 21.
Wnt signaling is dysregulated in many cancers and is therefore an attractive therapeutic target. The focus of drug development has recently shifted away from downstream inhibitors of β-catenin. Active inhibitors of Wnt secretion and Wnt/receptor interactions have been developed that are now entering clinical trials. Such agents include inhibitors of Wnt secretion, as well as recombinant proteins that minimize Wnt-Frizzled interactions. These new therapies arrive together with the recent insight that cancer-specific upregulation of Wnt receptors at the cell surface regulates cellular sensitivity to Wnts. Loss-of-function mutations in RNF43 or ZNRF3 and gain-of-function chromosome translocations involving RSPO2 and RSPO3 are surprisingly common and markedly increase Wnt/β-catenin signaling in response to secreted Wnts. These mutations may be predictive biomarkers to select patients responsive to newly developed upstream Wnt inhibitors.
Wnt信号通路在许多癌症中失调，因此是一个有吸引力的治疗靶点。药物开发的重点最近已从β-连环蛋白的下游抑制剂转移。目前已开发出Wnt分泌和Wnt/受体相互作用的活性抑制剂，这些抑制剂现已进入临床试验。此类药物包括Wnt分泌抑制剂，以及可减少Wnt-卷曲蛋白相互作用的重组蛋白。这些新疗法出现的同时，最近有研究发现，细胞表面Wnt受体的癌症特异性上调会调节细胞对Wnts的敏感性。RNF43或ZNRF3的功能丧失突变以及涉及RSPO2和RSPO3的功能获得性染色体易位出人意料地常见，并显著增强了对分泌型Wnts的Wnt/β-连环蛋白信号传导。这些突变可能是预测性生物标志物，用于选择对新开发的上游Wnt抑制剂有反应的患者。
