Bayley Rachel, Sweatman Ellie, Higgs Martin R
Both authors contributed equally.
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.
Cancer Drug Resist. 2023 Jan 4;6(1):35-44. doi: 10.20517/cdr.2022.73. eCollection 2023.
The clinical treatment of DNA-repair defective tumours has been revolutionised by the use of poly(ADP) ribose polymerase (PARP) inhibitors. However, the efficacy of these compounds is hampered by resistance, which is attributed to numerous mechanisms including rewiring of the DNA damage response to favour pathways that repair PARP inhibitor-mediated damage. Here, we comment on recent findings by our group identifying the lysine methyltransferase SETD1A as a novel factor that conveys PARPi resistance. We discuss the implications, with a particular focus on epigenetic modifications and H3K4 methylation. We also deliberate on the mechanisms responsible, the consequences for the refinement of PARP inhibitor use in the clinic, and future possibilities to circumvent drug resistance in DNA-repair deficient cancers.
聚（ADP）核糖聚合酶（PARP）抑制剂的使用彻底改变了DNA修复缺陷肿瘤的临床治疗方法。然而，这些化合物的疗效受到耐药性的阻碍，耐药性归因于多种机制，包括重新调整DNA损伤反应以支持修复PARP抑制剂介导损伤的途径。在此，我们对我们团队最近的发现发表评论，该发现确定赖氨酸甲基转移酶SETD1A是一种传递PARP抑制剂耐药性的新因子。我们讨论其影响，特别关注表观遗传修饰和H3K4甲基化。我们还思考了相关机制、对优化PARP抑制剂在临床中使用的影响，以及未来在DNA修复缺陷癌症中规避耐药性的可能性。
