前列腺癌是一种具有异质性特征的疾病，其可治疗性和治愈性取决于癌症的阶段。虽然前列腺癌通常是惰性的，但有些病例可能具有侵袭性，并演变成致命的转移性去势抵抗性前列腺癌 (mCRPC)。 mCRPC 患者的一个重要子集在 DNA 损伤修复 (DDR) 通路的组成部分中表现出种系和体细胞变异。最近，PARP 抑制剂 (PARPi) 在治疗携带 BRCA2 和其他 13 个对同源重组修复 (HRR) 途径很重要的 DDR 基因有害改变的 mCRPC 患者方面显示出了希望。这些抑制剂通过捕获 PARP 发挥作用，导致 PARP 活性受损并增加 DNA 损伤，最终通过合成致死导致细胞死亡。然而，对这些抑制剂的反应只能持续 3-4 个月，此后癌症就会对 PARPi 产生耐药性。癌细胞可以通过多种机制产生对 PARPi 的耐药性，例如 DNA 修复途径基因的二次回复突变、药物外流增加、PARP 表达丧失、HRR 重新激活、复制叉稳定性以及 Wnt/Catenin 和 ABCB1 途径的上调。克服 PARPi 耐药性是一个关键且复杂的过程，有两种可能的方法可以使耐药性变得敏感。第一种方法是通过化疗/放疗和联合治疗来增强 PARPi 药物的作用，而第二种方法则需要针对不同的信号通路。这篇综述文章重点介绍了 PARPi 在致死性前列腺癌中耐药机制的最新证据，并讨论了对 PARPi 没有反应的 DDR 基因改变的前列腺癌患者的其他治疗机会。版权所有 © 2024。由 Elsevier Inc. 出版。

Prostate cancer is a disease with heterogeneous characteristics, making its treatability and curability dependent on the cancer's stage. While prostate cancer is often indolent, some cases can be aggressive and evolve into metastatic castration-resistant prostate cancer (mCRPC), which is lethal. A significant subset of individuals with mCRPC exhibit germline and somatic variants in components of the DNA damage repair (DDR) pathway. Recently, PARP inhibitors (PARPi) have shown promise in treating mCRPC patients who carry deleterious alterations in BRCA2 and 13 other DDR genes that are important for the homologous recombination repair (HRR) pathway. These inhibitors function by trapping PARP, resulting in impaired PARP activity and increased DNA damage, ultimately leading to cell death through synthetic lethality. However, the response to these inhibitors only lasts for 3-4 months, after which the cancer becomes PARPi resistant. Cancer cells can develop resistance to PARPi through numerous mechanisms, such as secondary reversion mutations in DNA repair pathway genes, heightened drug efflux, loss of PARP expression, HRR reactivation, replication fork stability, and upregulation of Wnt/Catenin and ABCB1 pathways. Overcoming PARPi resistance is a critical and complex process, and there are two possible ways to sensitize the resistance. The first approach is to potentiate the PARPi agents through chemo/radiotherapy and combination therapy, while the second approach entails targeting different signaling pathways. This review article highlights the latest evidence on the resistance mechanism of PARPi in lethal prostate cancer and discusses additional therapeutic opportunities available for prostate cancer patients with DDR gene alterations who do not respond to PARPi.Copyright © 2024. Published by Elsevier Inc.