聚腺苷二磷酸核糖聚合酶抑制剂（PARPi）、BRCA 基因和空白：争议与未来研究。

PARPi, BRCA, and gaps: controversies and future research.

机构信息

Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland; Bern Center for Precision Medicine and Cancer Therapy Research Cluster, Department for Biomedical Research, University of Bern, 3012 Bern, Switzerland; Molecular Oncology and DNA Damage Response Laboratory, Department of Experimental Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy.

出版信息

Trends Cancer. 2024 Sep;10(9):857-869. doi: 10.1016/j.trecan.2024.06.008.

DOI:10.1016/j.trecan.2024.06.008

PMID:39004561

Abstract

In recent years, various poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been approved for the treatment of several cancers to target the vulnerability of homologous recombination (HR) deficiency (e.g., due to BRCA1/2 dysfunction). In this review we analyze the ongoing debates and recent breakthroughs in the use of PARPis for BRCA1/2-deficient cancers, juxtaposing the 'double-strand break (DSB)' and 'single-stranded DNA (ssDNA) gap' models of synthetic lethality induced by PARPis. We spotlight the complexity of this interaction, highlighting emerging research on the role of DNA polymerase theta (POLθ) and ssDNA gaps in shaping therapy responses. We scrutinize the clinical ramifications of these findings, especially concerning PARPi efficacy and resistance mechanisms, underscoring the heterogeneity of BRCA-mutated tumors and the urgent need for advanced research to bridge the gap between laboratory models and patient outcomes.

摘要

近年来，多种聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）已被批准用于治疗多种癌症，以靶向同源重组（HR）缺陷的脆弱性（例如，由于 BRCA1/2 功能障碍）。在这篇综述中，我们分析了 PARPi 用于 BRCA1/2 缺陷癌症的正在进行的争论和最新突破，并列了 PARPi 诱导的合成致死性的“双链断裂（DSB）”和“单链 DNA（ssDNA）缺口”模型。我们重点介绍了这种相互作用的复杂性，强调了关于 DNA 聚合酶θ（POLθ）和 ssDNA 缺口在塑造治疗反应中的作用的新兴研究。我们仔细研究了这些发现的临床意义，特别是关于 PARPi 疗效和耐药机制的意义，强调了 BRCA 突变肿瘤的异质性以及迫切需要进行高级研究，以缩小实验室模型和患者结果之间的差距。