PARP inhibitors in ovarian cancer: Mechanisms of resistance and implications to therapy

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair Pub Date : 2025-04-03 DOI:10.1016/j.dnarep.2025.103830

Sanat Kulkarni , Nethmin Seneviratne , Çağla Tosun , Srinivasan Madhusudan

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引用次数: 0

Abstract

Advanced epithelial ovarian cancer of the high-grade serous subtype (HGSOC) remains a significant clinical challenge due to the development of resistance to current platinum-based chemotherapies. PARP1/2 inhibitors (PARPi) exploit the well-characterised homologous recombination repair deficiency (HRD) in HGSOC and offer an effective targeted approach to treatment. Several clinical trials demonstrated that PARPi (olaparib, rucaparib, niraparib) significantly improved progression-free survival (PFS) in HGSOC in the recurrent maintenance setting. However, 40–70 % of patients develop Resistance to PARPi presenting an ongoing challenge in the clinic. Therefore, there is an unmet need for novel targeted therapies and biomarkers to identify intrinsic or acquired resistance to PARPi in ovarian cancer. Understanding the mechanisms of resistance to PARPi is crucial for identifying molecular vulnerabilities, developing effective biomarkers for patient stratification and guiding treatment decisions. Here, we summarise the current landscape of mechanisms associated with PARPi resistance such as restored homologous recombination repair functionality, replication fork stability and alterations to PARP1 and PARP2 and the DNA damage response. We highlight the role of circulating tumour DNA (ctDNA) in identifying acquired resistance biomarkers and its potential in guiding ‘real-time’ treatment decisions. Moreover, we explore other innovative treatment strategies aimed at overcoming specific resistance mechanisms, including the inhibition of ATR, WEE1 and POLQ. We also examine the role of PARPi rechallenge in patients with acquired resistance.

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卵巢癌中的PARP抑制剂：耐药机制及其对治疗的影响

高级浆液亚型（HGSOC）的晚期上皮性卵巢癌仍然是一个重大的临床挑战，由于目前铂基化疗的耐药发展。PARP1/2抑制剂（PARPi）利用了HGSOC中具有良好特征的同源重组修复缺陷（HRD），并提供了有效的靶向治疗方法。几项临床试验表明，PARPi （olaparib, rucaparib, niraparib）在复发性维持环境中显著改善了HGSOC的无进展生存（PFS）。然而，40-70 %的患者对PARPi产生耐药性，这在临床上是一个持续的挑战。因此，对新的靶向治疗和生物标志物的需求尚未得到满足，以确定卵巢癌对PARPi的内在或获得性耐药。了解PARPi耐药机制对于识别分子脆弱性、开发有效的生物标志物用于患者分层和指导治疗决策至关重要。在这里，我们总结了目前与PARPi抗性相关的机制，如恢复同源重组修复功能、复制叉稳定性、PARP1和PARP2的改变以及DNA损伤反应。我们强调循环肿瘤DNA （ctDNA）在识别获得性耐药生物标志物中的作用及其在指导“实时”治疗决策方面的潜力。此外，我们还探索了其他旨在克服特定耐药机制的创新治疗策略，包括抑制ATR、WEE1和POLQ。我们还研究了PARPi再挑战在获得性耐药患者中的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

DNA Repair 生物-毒理学

CiteScore

7.60

自引率

5.30%

发文量

审稿时长

59 days

期刊介绍： DNA Repair provides a forum for the comprehensive coverage of DNA repair and cellular responses to DNA damage. The journal publishes original observations on genetic, cellular, biochemical, structural and molecular aspects of DNA repair, mutagenesis, cell cycle regulation, apoptosis and other biological responses in cells exposed to genomic insult, as well as their relationship to human disease. DNA Repair publishes full-length research articles, brief reports on research, and reviews. The journal welcomes articles describing databases, methods and new technologies supporting research on DNA repair and responses to DNA damage. Letters to the Editor, hot topics and classics in DNA repair, historical reflections, book reviews and meeting reports also will be considered for publication.