近年来，各种聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPis）已被批准用于治疗多种癌症，以针对同源重组（HR）缺陷（例如，由于 BRCA1/2 功能障碍）的脆弱性。在这篇综述中，我们分析了使用 PARPis 治疗 BRCA1/2 缺陷型癌症的持续争论和最新突破，并将“双链断裂 (DSB)”和“单链 DNA (ssDNA) 缺口”合成致死模型并置由 PARPis 诱导。我们重点关注这种相互作用的复杂性，重点介绍关于 DNA 聚合酶 theta (POLθ) 和 ssDNA 间隙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影响，特别是关于 PARPi 功效和耐药机制，强调了 BRCA 突变肿瘤的异质性以及迫切需要进行高级研究来弥合实验室模型和患者结果之间的差距。版权所有 © 2024 ）。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.