TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in cancer cells without harming most normal cells. Currently, multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL (rhTRAIL) and agonistic antibodies that target death receptors (DRs) 4 or 5. It is encouraging that these products have shown a tolerated safety profile in early phase studies. However, their therapeutic potential is likely limited by the emergence of tumor drug resistance phenomena. Increasing evidence indicates that TRAIL DRs are deficient on the plasma membrane of some cancer cells despite their total protein expression. Notably, the lack of surface DR4/DR5 is sufficient to render cancers resistant to TRAIL-induced apoptosis, regardless of the status of other apoptosis signaling components. The current review highlights recent findings on the dynamic expression of TRAIL death receptors, including the regulatory roles of endocytosis, autophagy, and Ras GTPase-mediated signaling events. This information could aid in the identification of novel predictive biomarkers of tumor response as well as the development of combinational drugs to overcome or bypass tumor drug resistance to TRAIL receptor-targeted therapies.

中文翻译：

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癌细胞中TRAIL死亡受体的空间动力学。

TNF相关凋亡诱导配体（TRAIL）在不损害大多数正常细胞的情况下选择性诱导癌细胞凋亡。当前，正在进行多项临床试验以评估重组人TRAIL（rhTRAIL）和靶向死亡受体（DRs）4或5的激动性抗体的抗肿瘤活性。令人鼓舞的是，这些产品在早期研究中显示出可耐受的安全性。但是，它们的治疗潜力可能受到肿瘤耐药现象的出现的限制。越来越多的证据表明，尽管某些TRAIL DRs具有总蛋白表达，但它们在质膜上仍存在缺陷。值得注意的是，表面DR4 / DR5的缺乏足以使癌症对TRAIL诱导的细胞凋亡具有抵抗力，而与其他细胞凋亡信号传导元件的状态无关。本篇综述着重介绍了TRAIL死亡受体动态表达的最新发现，包括内吞作用，自噬和Ras GTPase介导的信号传导事件的调节作用。该信息可以帮助鉴定肿瘤反应的新的预测性生物标志物，以及开发用于克服或绕过肿瘤对TRAIL受体靶向疗法的耐药性的联合药物。