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,各种聚（ADP-核糖）聚合酶（PARP）抑制剂（PARP）已被批准用于治疗几种癌症，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，我们分析了在使用PARPis治疗BRCA1/2缺陷型癌症方面正在进行的辩论和最近的突破。并置“双链断裂(DSB)”和“单链DNA(ssDNA)缺口”模型的PARPis诱导的合成致死性。我们关注这种互动的复杂性，强调关于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后果，特别是关于PARPi的功效和抗性机制，强调了BRCA突变肿瘤的异质性以及迫切需要先进的研究来弥合实验室模型和患者预后之间的差距.
