Caracciolo Daniele, Riillo Caterina, Di Martino Maria Teresa, Tagliaferri Pierosandro, Tassone Pierfrancesco
Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, 88100 Catanzaro, Italy.
Cancers (Basel). 2021 Mar 19;13(6):1392. doi: 10.3390/cancers13061392.
Error-prone DNA repair pathways promote genomic instability which leads to the onset of cancer hallmarks by progressive genetic aberrations in tumor cells. The molecular mechanisms which foster this process remain mostly undefined, and breakthrough advancements are eagerly awaited. In this context, the alternative non-homologous end joining (Alt-NHEJ) pathway is considered a leading actor. Indeed, there is experimental evidence that up-regulation of major Alt-NHEJ components, such as LIG3, PolQ, and PARP1, occurs in different tumors, where they are often associated with disease progression and drug resistance. Moreover, the Alt-NHEJ addiction of cancer cells provides a promising target to be exploited by synthetic lethality approaches for the use of DNA damage response (DDR) inhibitors and even as a sensitizer to checkpoint-inhibitors immunotherapy by increasing the mutational load. In this review, we discuss recent findings highlighting the role of Alt-NHEJ as a promoter of genomic instability and, therefore, as new cancer's Achilles' heel to be therapeutically exploited in precision oncology.
易出错的DNA修复途径会促进基因组不稳定，而基因组不稳定会通过肿瘤细胞中逐渐累积的基因畸变导致癌症特征的出现。促进这一过程的分子机制大多仍不明确，人们急切期待着突破性进展。在这种情况下，替代性非同源末端连接（Alt-NHEJ）途径被认为是主要因素。确实，有实验证据表明，主要的Alt-NHEJ组分（如LIG3、PolQ和PARP1）在不同肿瘤中上调，它们常常与疾病进展和耐药性相关。此外，癌细胞对Alt-NHEJ的依赖性为合成致死方法提供了一个有前景的靶点，可用于使用DNA损伤反应（DDR）抑制剂，甚至通过增加突变负荷作为检查点抑制剂免疫疗法的增敏剂。在这篇综述中，我们讨论了最近的研究发现，这些发现突出了Alt-NHEJ作为基因组不稳定促进因子的作用，因此，它是精准肿瘤学中可用于治疗的新的癌症弱点。
