Clinical approaches to overcome PARP inhibitor resistance

IF 33.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2025-05-30 DOI:10.1186/s12943-025-02355-1

Yutian Zou, Hanqi Zhang, Pangzhou Chen, Jiayi Tang, Siwei Yang, Christophe Nicot, Ziyun Guan, Xing Li, Hailin Tang

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引用次数: 0

Abstract

PARP inhibitors have profoundly changed treatment options for cancers with homologous recombination repair defects, especially those carrying BRCA1/2 mutations. However, the development of resistance to these inhibitors presents a significant clinical challenge as it limits long-term effectiveness. This review provides an overview of the current understanding of resistance mechanisms to PARP inhibitors and explores strategies to overcome these challenges. We discuss the basis of synthetic lethality induced by PARP inhibitors and detail diverse resistance mechanisms affecting PARP inhibitors, including homologous recombination restoration, reduced PARP trapping, enhanced drug efflux, and replication fork stabilization. The review then considers clinical approaches to combat resistance, focusing on combination therapies with immune checkpoint inhibitors, DNA damage response inhibitors, and epigenetic drugs. We also highlight ongoing clinical trials and potential biomarkers for predicting treatment response and resistance. The review concludes by outlining future research directions, emphasizing the need for longitudinal studies, advanced resistance monitoring technologies, and the development of novel combination strategies. By tackling PARP inhibitor resistance, this review seeks to aid in the development of more effective cancer therapies, with the potential to improve outcomes for patients with homologous recombination-deficient tumors.

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克服PARP抑制剂耐药的临床途径

PARP抑制剂已经深刻地改变了具有同源重组修复缺陷的癌症的治疗选择，特别是那些携带BRCA1/2突变的癌症。然而，对这些抑制剂的耐药性的发展提出了一个重大的临床挑战，因为它限制了长期的有效性。本文综述了目前对PARP抑制剂耐药机制的理解，并探讨了克服这些挑战的策略。我们讨论了PARP抑制剂诱导的合成致死性的基础，并详细介绍了影响PARP抑制剂的多种耐药机制，包括同源重组恢复、减少PARP捕获、增强药物外排和复制叉稳定。然后，综述考虑了对抗耐药性的临床方法，重点是免疫检查点抑制剂、DNA损伤反应抑制剂和表观遗传药物的联合治疗。我们还强调了正在进行的临床试验和潜在的生物标志物，以预测治疗反应和耐药性。综述总结了未来的研究方向，强调了纵向研究、先进的耐药性监测技术和开发新的联合策略的必要性。通过解决PARP抑制剂耐药性，本综述旨在帮助开发更有效的癌症治疗方法，有可能改善同源重组缺陷肿瘤患者的预后。

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

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

期刊介绍： Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.