Xie Yijun, Xiao Di, Li Duo, Peng Mei, Peng Wei, Duan Huaxin, Yang Xiaoping
Department of Oncology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Normal University, Changsha, Hunan, China.
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Hunan Normal University, Changsha, Hunan, China.
Front Oncol. 2024 Aug 2;14:1441222. doi: 10.3389/fonc.2024.1441222. eCollection 2024.
Genomic instability stands out as a pivotal hallmark of cancer, and PARP inhibitors (PARPi) emerging as a groundbreaking class of targeted therapy drugs meticulously crafted to inhibit the repair of DNA single-strand breaks(SSB) in tumor cells. Currently, PARPi have been approved for the treatment of ovarian cancer, pancreatic cancer, breast cancer, and prostate cancer characterized by homologous recombination(HR) repair deficiencies due to mutations in BRCA1/2 or other DNA repair associated genes and acquiring the designation of breakthrough therapy. Nonetheless, PARPi exhibit limited efficacy in the majority of HR-proficient wild-type cancers. At present, the synergistic approach of combining PARPi with agents that induce HR defects, or with chemotherapy and radiotherapy to induce substantial DNA damage, significantly enhances the efficacy of PARPi in wild-type or HR-proficient patients, supporting extension the use of PARPi in HR proficient patients. Therefore, we have summarized the effects and mechanisms of the combined use of drugs with PARPi, including the combination of PARPi with HR defect-inducing drugs such as ATRi, CHKi, HR indirectly inducing drugs like VEGFRi, CDKi, immune checkpoint inhibitors and drugs instigating DNA damage such as chemotherapy or radiotherapy. In addition, this review discusses several ongoing clinical trials aimed at analyzing the clinical application potential of these combined treatment strategies.
基因组不稳定是癌症的一个关键标志，聚（ADP-核糖）聚合酶抑制剂（PARPi）作为一类开创性的靶向治疗药物脱颖而出，其精心设计用于抑制肿瘤细胞中DNA单链断裂（SSB）的修复。目前，PARPi已被批准用于治疗因BRCA1/2或其他DNA修复相关基因突变导致同源重组（HR）修复缺陷的卵巢癌、胰腺癌、乳腺癌和前列腺癌，并获得了突破性疗法的称号。然而，PARPi在大多数HR功能正常的野生型癌症中疗效有限。目前，将PARPi与诱导HR缺陷的药物，或与化疗和放疗联合以诱导大量DNA损伤的协同方法，显著提高了PARPi在野生型或HR功能正常患者中的疗效，支持在HR功能正常患者中扩大PARPi的使用。因此，我们总结了PARPi与其他药物联合使用的效果和机制，包括PARPi与诱导HR缺陷的药物（如ATR抑制剂、CHK抑制剂）、间接诱导HR的药物（如VEGFR抑制剂、CDK抑制剂）、免疫检查点抑制剂以及引发DNA损伤的药物（如化疗或放疗）的联合。此外，本综述还讨论了一些正在进行的临床试验，旨在分析这些联合治疗策略的临床应用潜力。
