Thorburn Andrew, Behbakht Kian, Ford Heide
Department of Pharmacology, University of Colorado Denver, School of Medicine, Aurora, CO 80010, USA.
Drug Resist Updat. 2008 Feb-Apr;11(1-2):17-24. doi: 10.1016/j.drup.2008.02.001. Epub 2008 Apr 18.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors are attractive therapeutic targets in cancer because agents that activate these receptors directly induce tumor cell apoptosis and have low toxicity to normal tissues. Consequently, several different drugs that target these receptors (recombinant TRAIL and various agonistic antibodies that activate one of the two TRAIL receptors) have been developed and are being tested in human clinical trials. However, in vitro and in vivo data suggest that resistance to these agents may limit their clinical effectiveness. In this review, we discuss recent findings about some of the ways these resistance mechanisms arise, potential biomarkers to identify TRAIL resistance in patients (Six1, GALNT14, XIAP, certain microRNAs) and potential ways to circumvent resistance and resensitize tumors.
肿瘤坏死因子相关凋亡诱导配体(TRAIL)受体是癌症治疗中颇具吸引力的靶点,因为直接激活这些受体的药物可直接诱导肿瘤细胞凋亡,且对正常组织毒性较低。因此,已经开发出几种靶向这些受体的不同药物(重组TRAIL和激活两种TRAIL受体之一的各种激动性抗体),并正在进行人体临床试验。然而,体外和体内数据表明,对这些药物的耐药性可能会限制其临床疗效。在这篇综述中,我们讨论了关于这些耐药机制产生的一些方式、识别患者TRAIL耐药性的潜在生物标志物(Six1、GALNT14、XIAP、某些微小RNA)以及规避耐药性和使肿瘤重新敏感化的潜在方法的最新研究结果。