Harnessing TRAIL-induced cell death for cancer therapy: a long walk with thrilling discoveries.
Harnessing TRAIL-induced cell death for cancer therapy: a long walk with thrilling discoveries.
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DOI：
10.1038/s41418-022-01059-z
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发表时间：
2023-02
影响因子：
12.4
通讯作者：
Walczak, Henning
中科院分区：
文献类型：
--
作者：
Montinaro, Antonella;Walczak, Henning
肿瘤坏死因子（TNF）相关的凋亡诱导配体（TRAIL）可以在体外和体内诱导多种癌细胞凋亡，重要的是不杀死任何必需的正常细胞。这些发现为开发用于癌症治疗的TRAIL受体激动剂（TRAs）奠定了基础。然而，迄今为止，用不同类型的TRA进行的临床试验仅提供有限的治疗益处，因为分别选择的激动剂显示出不足的抗癌活性或毒性迹象，或者没有采用正确的包含TRAIL的组合疗法。因此，在这篇综述中，我们将讨论TRAIL耐药的分子决定因素，迄今为止发现的最有前途的TRAIL增敏剂，重要的是，这些药物中的任何一种是否也可以证明在常规一线治疗后癌症复发的治疗有效。我们还将讨论高活性非免疫原性下一代TRA的临床开发方面的最新进展。基于此，我们接下来提出了如何成功克服TRAIL抗性，从而导致未来可能开发基于我们目前对生物学TRAIL诱导细胞死亡的理解的高效癌症选择性组合疗法。这类疗法可能提供解决有效癌症治疗的主要障碍之一的机会，即克服化疗和/或靶向治疗抗性。即使这仅对某些类型的治疗耐药性和特定类型的癌症是可以实现的，这也将是一个重大而有意义的成就。
Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) can induce apoptosis in a wide variety of cancer cells, both in vitro and in vivo, importantly without killing any essential normal cells. These findings formed the basis for the development of TRAIL-receptor agonists (TRAs) for cancer therapy. However, clinical trials conducted with different types of TRAs have, thus far, afforded only limited therapeutic benefit, as either the respectively chosen agonist showed insufficient anticancer activity or signs of toxicity, or the right TRAIL-comprising combination therapy was not employed. Therefore, in this review we will discuss molecular determinants of TRAIL resistance, the most promising TRAIL-sensitizing agents discovered to date and, importantly, whether any of these could also prove therapeutically efficacious upon cancer relapse following conventional first-line therapies. We will also discuss the more recent progress made with regards to the clinical development of highly active non-immunogenic next generation TRAs. Based thereupon, we next propose how TRAIL resistance might be successfully overcome, leading to the possible future development of highly potent, cancer-selective combination therapies that are based on our current understanding of biology TRAIL-induced cell death. It is possible that such therapies may offer the opportunity to tackle one of the major current obstacles to effective cancer therapy, namely overcoming chemo- and/or targeted-therapy resistance. Even if this were achievable only for certain types of therapy resistance and only for particular types of cancer, this would be a significant and meaningful achievement.
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