靶向DNA损伤反应途径:PARP抑制剂抗肿瘤治疗研究进展

Targeting DNA damage response pathway: recent progress of PARP inhibitors in cancer therapy

细胞在长期进化过程中形成的复杂的DNA损伤反应防御机制是维护基因组稳定性的重要途径,DNA损伤反应通路缺陷可导致包括肿瘤在内的多种疾病的发生。DNA损伤反应通路是一个复杂的信号通路,包括DNA损伤修复、凋亡、细胞周期调控等,DNA损伤反应通路已经成为新的抗肿瘤药物靶点。目前,已经开发多种DNA损伤反应通路相关的抑制剂,特别是对BRCA1和BRCA2基因突变的肿瘤,利用协同致死现象而开发的聚腺苷二磷酸核糖聚合酶抑制剂广泛应用于肿瘤个体化治疗。该文重点对DNA损伤反应通路抑制剂中的聚腺苷二磷酸核糖聚合酶抑制剂的作用分子机制、临床治疗、耐药性以及面临的挑战进行综述。

Genomic instability is one of the most pervasive characteristics of cancer cells,and DNA damage response( DDR)pathway plays a crucial role in genomic stability. The DDR pathway is a complex signaling network,which involves cell DNA repair,apoptosis and cell cycle regulation. Deficiencies in these repair pathways can result in several different genetic disorders,including cancer. Targeted therapy based on inhibiting the DDR pathway in cancers offers a novel therapy strategy for patients with tumors lacking specific DDR functions. Many small-molecule compounds targeting DDR pathway are typically developed for solid cancer therapy. The poly( ADP-ribose) polymerase( PARP) inhibitor is a kind of DDR inhibitors which exploits the principle of synthetic lethality to selectively kill cancer cells.This review highlights the molecular mechanisms of PARP inhibitor action,the progress of PARP inhibitors in cancer therapy,drug resistance and the challenge of PARP inhibitor in the future.