Navigating PARP Inhibitor Resistance in Ovarian Cancer: Bridging Mechanistic Insights To Clinical Translation.

IF 4.7 2区医学 Q2 ONCOLOGY

Current Treatment Options in Oncology Pub Date : 2025-09-01 Epub Date: 2025-08-19 DOI:10.1007/s11864-025-01347-z

Ziyi Wang, Yuting Liu, Qing Yang

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引用次数: 0

Abstract

Opinion statement: PARP inhibitors (PARPi) are increasingly vital in treating, particularly in individuals exhibiting homologous recombination deficiency (HRD), harnessing synthetic lethality to target tumor cells. However, PARPi resistance severely restricts their sustained efficacy, posing a significant clinical obstacle requiring a detailed exploration of its mechanisms and solutions. This review elucidates the underlying mechanisms of PARPi resistance, assesses biomarker-driven predictive tools, and explores novel strategies to improve therapeutic outcomes. This review critically assesses biomarker-driven strategies for resistance prediction, such as genomic profiling, functional assays, dynamic circulating tumor DNA (ctDNA) monitoring, and emerging markers, to refine patient stratification. Moreover, this review systematically dissects PARPi resistance, including genomic alterations, homologous recombination (HR) restoration, replication fork stabilization, enhanced drug efflux, reduced PARP1 trapping, and microenvironmental influences. In addition, therapeutic tactics to prevent or overcome resistance are evaluated, encompassing sequential PARPi use, combinations with chemotherapy, immunotherapy, antiangiogenic agents, and DNA damage response (DDR) inhibitors, alongside innovative approaches like antibody-drug conjugates (ADCs). Bridging mechanistic and clinical perspectives, this review promotes a multidisciplinary approach to optimize PARPi-based treatments, addressing current challenges in ovarian cancer management.

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在卵巢癌中导航PARP抑制剂耐药性：将机制见解连接到临床转化。

观点声明：PARP抑制剂（PARPi）在治疗中越来越重要，特别是在表现同源重组缺陷（HRD）的个体中，利用合成致死性靶向肿瘤细胞。然而，PARPi耐药严重限制了其持续疗效，这给临床带来了重大障碍，需要详细探索其机制和解决方案。这篇综述阐明了PARPi耐药的潜在机制，评估了生物标志物驱动的预测工具，并探索了改善治疗结果的新策略。这篇综述批判性地评估了生物标志物驱动的耐药预测策略，如基因组分析、功能分析、动态循环肿瘤DNA （ctDNA）监测和新兴标志物，以完善患者分层。此外，本文系统剖析了PARPi耐药性，包括基因组改变、同源重组（HR）恢复、复制叉稳定、药物外排增强、PARP1捕获减少和微环境影响。此外，还评估了预防或克服耐药性的治疗策略，包括顺序使用PARPi，与化疗、免疫治疗、抗血管生成药物和DNA损伤反应（DDR）抑制剂联合使用，以及抗体-药物偶联物（adc）等创新方法。结合机制和临床观点，本综述促进了一种多学科方法来优化基于parpi的治疗，解决当前卵巢癌管理中的挑战。

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

Current Treatment Options in Oncology ONCOLOGY-

CiteScore

7.10

自引率

0.00%

发文量

113

审稿时长

>12 weeks

期刊介绍： This journal aims to review the most important, recently published treatment option advances in the field of oncology. By providing clear, insightful, balanced contributions by international experts, the journal intends to facilitate worldwide approaches to cancer treatment. We accomplish this aim by appointing international authorities to serve as Section Editors in key subject areas, such as endocrine tumors, lymphomas, neuro-oncology, and cancers of the breast, head and neck, lung, skin, gastrointestinal tract, and genitourinary region. Section Editors, in turn, select topics for which leading experts contribute comprehensive review articles that emphasize new developments and recently published papers of major importance, highlighted by annotated reference lists. We also provide commentaries from well-known oncologists, and an international Editorial Board reviews the annual table of contents, suggests articles of special interest to their country/region, and ensures that topics are current and include emerging research.