PARP 和 EZH2 联合抑制癌症治疗：现状、机遇和挑战。,Frontiers in Pharmacology

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PARP 和 EZH2 联合抑制癌症治疗：现状、机遇和挑战。
Frontiers in Pharmacology ( IF 4.4 ) Pub Date : 2022-10-03 , DOI: 10.3389/fphar.2022.965244
Xi Zhang ₁ , Xiao Huo _{2,

3} , Hongyan Guo ₁ , Lixiang Xue _{2,

3}

Affiliation

具有 BRCA1/2 突变或同源重组修复缺陷的肿瘤通过合成致死机制对 PARP 抑制剂敏感。目前有几种 PARP 抑制剂在临床实践中被批准用于卵巢癌、乳腺癌和胰腺癌。然而，超过 40% 的 BRCA1/2 突变患者对 PARP 抑制剂不敏感，这引起了人们对 PARP 耐药机制和致敏方案的关注。PARP抑制剂耐药与同源重组修复、DNA复制叉的稳定性、PARylation和表观遗传修饰有关。表观遗传学研究已成为PARP抑制剂耐药性研究的热点。作为组蛋白甲基化介导的重要转录表观遗传调控因子，EZH2 通过 DNA 同源重组、DNA 复制、翻译后修饰、肿瘤免疫等方面。EZH2抑制剂刚刚从实验室转移到床边，但在癌症治疗中的组合方案尚未得到充分探索。最近，基于 PROTAC 技术结合 PARP 抑制剂和 EZH2 抑制剂的革命性药物设计揭示了 PARP 抑制剂耐药性的解决。本综述总结了 EZH2 和 PARP 之间的相互作用，提出了 EZH2 抑制剂潜在的 PARP 抑制剂致敏作用，并进一步讨论了受益于 EZH2 抑制剂和 PARP 抑制剂组合的潜在人群。但癌症治疗中的联合方案尚未得到充分探索。最近，基于 PROTAC 技术结合 PARP 抑制剂和 EZH2 抑制剂的革命性药物设计揭示了 PARP 抑制剂耐药性的解决。本综述总结了 EZH2 和 PARP 之间的相互作用，提出了 EZH2 抑制剂潜在的 PARP 抑制剂致敏作用，并进一步讨论了受益于 EZH2 抑制剂和 PARP 抑制剂组合的潜在人群。但癌症治疗中的联合方案尚未得到充分探索。最近，基于 PROTAC 技术结合 PARP 抑制剂和 EZH2 抑制剂的革命性药物设计揭示了 PARP 抑制剂耐药性的解决。本综述总结了 EZH2 和 PARP 之间的相互作用，提出了 EZH2 抑制剂潜在的 PARP 抑制剂致敏作用，并进一步讨论了受益于 EZH2 抑制剂和 PARP 抑制剂组合的潜在人群。

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Combined inhibition of PARP and EZH2 for cancer treatment: Current status, opportunities, and challenges.

Tumors with BRCA1/2 mutations or homologous recombination repair defects are sensitive to PARP inhibitors through the mechanism of synthetic lethality. Several PARP inhibitors are currently approved for ovarian, breast and pancreatic cancer in clinical practice. However, more than 40% of patients with BRCA1/2 mutations are insensitive to PARP inhibitors, which has aroused attention to the mechanism of PARP resistance and sensitization schemes. PARP inhibitor resistance is related to homologous recombination repair, stability of DNA replication forks, PARylation and epigenetic modification. Studies on epigenetics have become the hotspots of research on PARP inhibitor resistance. As an important epigenetic regulator of transcription mediated by histone methylation, EZH2 interacts with PARP through DNA homologous recombination, DNA replication, posttranslational modification, tumor immunity and other aspects. EZH2 inhibitors have been just shifting from the bench to the bedside, but the combination scheme in cancer therapy has not been fully explored yet. Recently, a revolutionary drug design combining PARP inhibitors and EZH2 inhibitors based on PROTAC techniques has shed light on the resolution of PARP inhibitor resistance. This review summarizes the interactions between EZH2 and PARP, suggests the potential PARP inhibitor sensitization effect of EZH2 inhibitors, and further discusses the potential populations that benefit from the combination of EZH2 inhibitors and PARP inhibitors.

更新日期：2022-10-03

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