胃癌（GC）是一种致命的疾病，总体生存率较差，治疗选择有限。 GC 中经常发生遗传改变，例如富含染色质重塑基因 AT 的相互作用域 1 A (ARID1A) 的突变和/或缺失。尽管 ARID1A 突变/缺失不是常规治疗的药物靶点，但基于合成致死方法的新治疗策略可能对治疗 ARID1A 缺陷型癌症有效。在 ARID1A 同基因 GC 细胞中筛选了包含 551 种化合物的激酶抑制剂库诱导合成致死效应的能力。验证了所选命中的活性，并研究了最有效的候选药物 AKT 抑制剂 AD5363 (capivasertib) 在 ARID1A 缺陷诱导合成致死方面的机制。在对 551 种不同的蛋白激酶抑制剂进行了稳健的脆弱性筛选后，我们确定了AKT 抑制剂 AZD5363 是抑制 ARID1A-/- 细胞活力的最有效的先导化合物。在 GC 细胞模型系统和异种移植模型中均验证了 ARID1A 表达缺失和 AZD5363 抑制 AKT 之间的综合致死率。从机制上讲，AZD5363 治疗通过激活 Caspase-3/GSDME 途径诱导 ARID1A 缺陷的 GC 细胞焦亡细胞死亡。此外，ARID1A 占据 AKT 基因启动子并负向调节其转录，因此 ARID1A 缺陷的 GC 细胞表现出 AKT 表达和磷酸化增加。我们的研究证明了 ARID1A 缺失和 AKT 抑制之间新的合成致死相互作用和独特机制，这可能提供对 ARID1A 缺陷型 GC 患者进行靶向治疗的治疗和机制原理，这些患者最有可能对 AZD5363 治疗有益。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Gastric cancer (GC) is a deadly disease with poor overall survival and limited therapeutic options. Genetic alterations such as mutations and/or deletions in chromatin remodeling gene AT-rich interactive domain 1 A (ARID1A) occur frequently in GC. Although ARID1A mutations/deletions are not a druggable target for conventional treatments, novel therapeutic strategies based on a synthetic lethal approach may be effective for the treatment of ARID1A-deficient cancers.A kinase inhibitor library containing 551 compounds was screened in ARID1A isogenic GC cells for the ability to induce synthetic lethality effect. Selected hits' activity was validated, and the mechanism of the most potent candidate drug, AKT inhibitor AD5363 (capivasertib), on induction of the synthetic lethality with ARID1A deficiency was investigated.After robust vulnerability screening of 551 diverse protein kinase inhibitors, we identified the AKT inhibitor AZD5363 as being the most potent lead compound in inhibiting viability of ARID1A-/- cells. A synthetic lethality between loss of ARID1A expression and AKT inhibition by AZD5363 was validated in both GC cell model system and xenograft model. Mechanistically, AZD5363 treatment induced pyroptotic cell death in ARID1A-deficient GC cells through activation of the Caspase-3/GSDME pathway. Furthermore, ARID1A occupied the AKT gene promoter and regulated its transcription negatively, thus the GC cells deficient in ARID1A showed increased expression and phosphorylation of AKT.Our study demonstrates a novel synthetic lethality interaction and unique mechanism between ARID1A loss and AKT inhibition, which may provide a therapeutic and mechanistic rationale for targeted therapy on patients with ARID1A-defective GC who are most likely to be beneficial to AZD5363 treatment.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.