文章：

利用合成致死效应揭示胃癌潜在治疗靶点

Leveraging synthetic lethality to uncover potential therapeutic target in gastric cancer 

原文发布日期：2023-12-01 

英文摘要：

Since trastuzumab was approved in 2012 for the first-line treatment of gastric cancer (GC), no significant advancement in GC targeted therapies has occurred. Synthetic lethality refers to the concept that simultaneous dysfunction of a pair of genes results in a lethal effect on cells, while the loss of an individual gene does not cause this effect. Through exploiting synthetic lethality, novel targeted therapies can be developed for the individualized treatment of GC. In this study, we proposed a computational strategy named Gastric cancer Specific Synthetic Lethality inference (GSSL) to identify synthetic lethal interactions in GC. GSSL analysis was used to infer probable synthetic lethality in GC using four accessible clinical datasets. In addition, prediction results were confirmed by experiments. GSSL analysis identified a total of 34 candidate synthetic lethal pairs, which included 33 unique targets. Among the synthetic lethal gene pairs, TP53-CHEK1 was selected for further experimental validation. Both computational and experimental results indicated that inhibiting CHEK1 could be a potential therapeutic strategy for GC patients with TP53 mutation. Meanwhile, in vitro experimental validation of two novel synthetic lethal pairs TP53-AURKB and ARID1A-EP300 further proved the universality and reliability of GSSL. Collectively, GSSL has been shown to be a reliable and feasible method for comprehensive analysis of inferring synthetic lethal interactions of GC, which may offer novel insight into the precision medicine and individualized treatment of GC. 

摘要翻译：

自2012年曲妥珠单抗获批用于胃癌一线治疗以来，胃癌靶向治疗领域未取得重大进展。合成致死是指一对基因同时失活会导致细胞死亡，而单个基因缺失则不会产生该效应的概念。通过利用合成致死原理，可开发新型靶向治疗方法用于胃癌个体化治疗。本研究提出名为"胃癌特异性合成致死推断"（GSSL）的计算策略，用于识别胃癌中的合成致死相互作用。该研究利用四个可公开获取的临床数据集，通过GSSL分析推断胃癌中可能的合成致死现象，并通过实验验证预测结果。GSSL分析共鉴定出34对候选合成致死基因对，涉及33个独特靶点。在合成致死基因对中，我们选择TP53-CHEK1进行进一步实验验证。计算和实验结果均表明，抑制CHEK1可能成为TP53突变胃癌患者的潜在治疗策略。同时，两个新型合成致死对TP53-AURKB和ARID1A-EP300的体外实验验证进一步证明了GSSL方法的普适性和可靠性。综上所述，GSSL被证明是推断胃癌合成致死相互作用的可靠且可行的综合分析方​​法，可能为胃癌精准医疗和个体化治疗提供新见解。

原文链接：

Leveraging synthetic lethality to uncover potential therapeutic target in gastric cancer