PARP抑制剂在乳腺癌中的作用机制及耐药性相关研究进展

Research Advances in Mechanism of Action and Drug Resistance of PARP Inhibitor in Breast Cancer

乳腺癌作为女性最常见的恶性肿瘤,严重威胁女性的生命和健康,其中携带乳腺癌易感基因突变乳腺癌患者的基因组具有不稳定性。聚腺苷二磷酸核糖聚合酶(PARP)在基因损伤应答、调节细胞凋亡、维持基因组稳定性中发挥十分重要的作用。而PARP抑制剂可以通过影响PARP的功能,对DNA的修复过程造成阻碍,在治疗DNA同源重组(HR)修复缺陷肿瘤(如乳腺癌、卵巢癌、胰腺癌)患者中取得巨大进展。但PARP抑制剂耐药人群的不断增加,影响了其疗效。PARP抑制剂的耐药机制主要包括HR的恢复、DNA复制叉的稳定、药物外排蛋白的过表达、回复突变、表观遗传的修饰等,分析总结这些耐药机制不仅可以提高人们对PARP抑制剂的认识,还可以为未来临床应用提供参考。

As the most common malignant tumor in women,breast cancer poses a serious threat to women′s life and health.The genome of the patients carrying breast cancer susceptibility gene mutations is unstable.Poly(ADP-ribose)polymerase(PARP)plays an important role in gene damage response,regulation of apoptosis and maintenance of genomic stability.And PARP inhibitors can affect the function of PARP and obstruct the DNA repair process,which has made great progress in treating patients with tumors with defective DNA homologous recombination(HR)repair,such as breast,ovarian and pancreatic cancers.However,due to the increasing of PARP inhibitors resistant population,the efficacy of PARR inhibitors is affected.The drug resistance mechanisms of PARP inhibitors mainly include the recovery of HR,the stability of DNA replication fork,the overexpression of drug efflux protein,reverse mutation,epigenetic modification,etc.,and analyzing and summarizing these drug resistance mechanisms can not only improve people′s understanding of PARP inhibitors,but also provide reference for future clinical application.