文章：

Polθ：同源重组缺陷型肿瘤中新兴起的合成致死搭档

Polθ: emerging synthetic lethal partner in homologous recombination-deficient tumors

原文发布日期：2024-08-09 

英文摘要：

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.

摘要翻译：

合成致死（SL）领域最显著的发现是同源重组修复（HR）相关基因（如BRCA1/2）缺陷肿瘤对PARP抑制剂（PARPis）的超敏反应。尽管初期对PARPi有治疗反应，但BRCA1/2基因与PARPi之间的合成致死作用存在不完全外显率。因此，相当一部分HR缺陷肿瘤会出现固有或获得性耐药，这成为临床研究的关键挑战。扩展的合成致死概念正在开辟新途径，涵盖新型遗传相互作用形式——不仅研究传统成对基因的合成致死，还探索调控相同必需细胞生存功能的生物通路间的合成致死关系。近期研究表明，HR通路与θ介导的末端连接（TMEJ）通路存在合成致死关系。DNA聚合酶θ（Polθ）由POLQ基因编码，是TMEJ通路的核心组分。当非同源末端连接（NHEJ）和HR通路受损时，这种固有的易错备份通路可修复切除性双链断裂（DSBs）。Polθ在正常组织中广泛表达，在多种癌症中过表达，通常与不良预后和较短无复发生存期相关。值得注意的是，HR缺陷肿瘤细胞呈现易错TMEJ通路的特征性突变标志。根据这一发现，HR蛋白（如BRCA1或BRCA2）的缺失会增强TMEJ特异性基因组特征，表明POLQ基因缺失与HR基因缺失之间存在合成致死相互作用，这使得Polθ作为BRCA1/2相关肿瘤潜在治疗靶点的研究价值日益凸显。本综述总结了POLQ与HR基因在DNA双链断裂修复中的协同作用，利用Polθ抑制剂治疗HR缺陷肿瘤及克服BRCA逆转突变所致治疗耐药的早期临床试验进展，以及Polθ的新多效性功能，为开发新型合成致死策略奠定基础。

原文链接：

Polθ: emerging synthetic lethal partner in homologous recombination-deficient tumors