Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Nat Rev Cancer. 2017 May 24;17(6):352-366. doi: 10.1038/nrc.2017.28.
The discovery that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis of cancer cells without causing toxicity in mice has led to the in-depth study of pro-apoptotic TRAIL receptor (TRAIL-R) signalling and the development of biotherapeutic drug candidates that activate TRAIL-Rs. The outcome of clinical trials with these TRAIL-R agonists has, however, been disappointing so far. Recent evidence indicates that many cancers, in addition to being TRAIL resistant, use the endogenous TRAIL-TRAIL-R system to their own advantage. However, novel insight on two fronts - how resistance of cancer cells to TRAIL-based pro-apoptotic therapies might be overcome, and how the pro-tumorigenic effects of endogenous TRAIL might be countered - gives reasonable hope that the TRAIL system can be harnessed to treat cancer. In this Review we assess the status quo of our understanding of the biology of the TRAIL-TRAIL-R system - as well as the gaps therein - and discuss the opportunities and challenges in effectively targeting this pathway.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）可诱导癌细胞凋亡而不引起小鼠毒性，这一发现促使人们深入研究促凋亡 TRAIL 受体（TRAIL-R）信号转导，并开发了激活 TRAIL-R 的生物治疗药物候选物。然而，这些 TRAIL-R 激动剂的临床试验结果迄今令人失望。最近的证据表明，除了对 TRAIL 具有抗性外，许多癌症还利用内源性 TRAIL-TRAIL-R 系统为自身谋利。然而，在两个方面有了新的认识——如何克服癌细胞对基于 TRAIL 的促凋亡疗法的抗性，以及如何对抗内源性 TRAIL 的促肿瘤作用——这给人以合理的希望，即可以利用 TRAIL 系统来治疗癌症。在这篇综述中，我们评估了我们对 TRAIL-TRAIL-R 系统生物学的理解现状——以及其中的差距——并讨论了有效靶向该途径的机会和挑战。
