The genetic concept of synthetic lethality provides a framework for identifying genotype-selective anticancer agents. In this approach, changes in cellular physiology that arise as a consequence of oncogene activation or tumor suppressor gene loss, rather than oncoproteins themselves, are targeted to achieve tumor selectivity. Here we show that agonists of the TRAIL death receptor DR5 potently induce apoptosis in human cells overexpressing the MYC oncogene, both in vitro and as tumor xenografts in vivo. MYC sensitizes cells to DR5 in a p53-independent manner by upregulating DR5 cell surface levels and stimulating autocatalytic processing of procaspase-8. These results identify a novel mechanism by which MYC sensitizes cells to apoptosis and validate DR5 agonists as potential MYC-selective cancer therapeutics.

中文翻译：

---

通过激活DR5死亡受体途径合成的MYC致死靶向。

合成杀伤力的遗传概念为鉴定基因型选择性抗癌药提供了框架。在这种方法中，目标是达到肿瘤选择性，而不是癌蛋白本身，这是由于癌基因激活或肿瘤抑制基因丢失而引起的细胞生理变化。在这里，我们显示TRAIL死亡受体DR5的激动剂在体外和体内肿瘤异种移植中均能有效诱导过度表达MYC癌基因的人细胞凋亡。MYC通过上调DR5细胞表面水平并刺激procaspase-8的自催化过程，以p53独立的方式使细胞对DR5敏感。这些结果确定了一种新的机制，MYC通过该机制使细胞对细胞凋亡敏感，并验证DR5激动剂是潜在的MYC选择性癌症治疗剂。