合成致死 (SL) 领域最引人注目的发现是，含有同源修复 (HR) 基因缺陷（例如 BRCA1/2）的肿瘤对 PARP 抑制剂 (PARPis) 过敏。尽管最初对 PARPi 有反应，但 BRCA1/2 基因和 PARPi 之间合成致死相互作用的外显率并不完整。因此，很大一部分 HR 缺陷肿瘤会经历内在或获得性耐药，这是临床研究的一个关键挑战。 SL 的扩展概念正在开辟新的途径，包括新形式的遗传相互作用，不仅研究成对基因的传统 SL，还研究调节相同基本生存细胞功能的生物途径之间的 SL。在此背景下，最近的研究表明 HR 和 theta 介导的末端连接 (TMEJ) 途径表现出 SL。 DNA 聚合酶 theta (Polθ) 由 POLQ 基因编码，是 TMEJ 的关键组成部分，TMEJ 是一种重要的备用途径，具有本质诱变性，可在非同源末端连接 (NHEJ) 和连接时修复切除的双链断裂 (DSB)。人力资源受损。 Polθ 在正常组织中广泛表达，在多种癌症中过度表达，通常与不良预后和较短的无复发生存期相关。值得注意的是，HR 缺陷的肿瘤细胞呈现出容易出错的 TMEJ 通路的特征突变特征。根据这一观察，HR 蛋白（例如 BRCA1 或 BRCA2）的丢失有助于增加 TMEJ 特异性基因组图谱，表明 POLQ 和 HR 基因丢失之间存在合成致死相互作用，并导致人们对 Polθ 作为一种新的治疗方法产生了兴趣。 BRCA1/2 相关肿瘤的潜在治疗靶点。这篇综述总结了 POLQ 和 HR 基因在 DNA DSB 修复中的共同作用、使用 Polθ 抑制剂治疗 HR 缺陷性肿瘤并克服 BRCA 回复突变的早期临床试验负责治疗耐药性，以及 Polθ 的新颖多效性，为开发未探索的合成致死策略铺平了道路。© 2024。作者。

The most remarkable finding in synthetic lethality (SL) is the hypersensitivity to PARP inhibitors (PARPis) of the tumors harboring defects in genes involved in homologous repair (HR) such as BRCA1/2. Despite initial responsiveness to PARPi, the penetrance of the synthetic lethal interactions between BRCA1/2 genes and PARPi is incomplete. Thus, a significant proportion of HR-defective tumors experience intrinsic or acquired resistance, representing a key challenge of clinical research. An expanded concept of SL is opening new ways and includes novel forms of genetic interactions, investigating not only traditional SL of pairs genes but also SL between biological pathways that regulate the same essential survival cell function. In this context, recent research showed that HR and theta-mediated end-joining (TMEJ) pathways exhibit SL. DNA polymerase theta (Polθ) is encoded by the POLQ gene and is a key component of the TMEJ, an essential backup pathway, intrinsically mutagenic, to repair resected double-strand breaks (DSBs) when the non-homologous end joining (NHEJ) and HR are impaired. Polθ is broadly expressed in normal tissues, overexpressed in several cancers, and typically associated with poor outcomes and shorter relapse-free survival. Notably, HR-deficient tumor cells present the characteristic mutational signatures of the error-prone TMEJ pathway. According to this observation, the loss of HR proteins, such as BRCA1 or BRCA2, contributes to increasing the TMEJ-specific genomic profile, suggesting synthetic lethal interactions between loss of the POLQ and HR genes, and resulting in the emerging interest for Polθ as a potential therapeutic target in BRCA1/2-associated tumors.This review summarizes the converging roles of the POLQ and HR genes in DNA DSB repair, the early-stage clinical trials using Polθ inhibitor to treat HR-defective tumors and to overcome BRCA-reversion mutations responsible for therapeutic resistance, and the novel pleiotropic effects of Polθ, paving the way for the development of unexplored synthetic lethality strategies.© 2024. The Author(s).