PI3K/AKT信号通路在胃癌（GC）中频繁活化；但是，在临床试验中，AKT抑制剂对未经选择的GC患者无效。在约30％的GC患者中发现的AT富集互动域1A（ARID1A）突变会激活PI3K/AKT信号传导，表明针对ARID1A缺陷激活的PI3K/AKT通路是ARID1A缺陷性GC的治疗候选药物。使用细胞存活和克隆形成实验评估了AKT抑制剂对ARID1A缺陷和ARID1A敲除ARID1A-WT GC细胞以及HER2阳性和HER2阴性GC的影响。访问癌症基因组图谱cBioPortal和基因表达芯片数据库确定GC细胞生长对PI3K/AKT信号通路依赖的程度。AKT抑制剂减少了ARID1A缺陷细胞的存活率，且在ARID1A缺陷/HER2阴性GC细胞中抑制作用更大。生物信息学数据表明，在ARID1A缺陷/HER2阴性GC细胞中，PI3K/AKT信号传导对增殖和存活的作用要大于在ARID1A缺陷/HER2阳性细胞中，并支持AKT抑制剂的更高治疗效果。AKT抑制剂对细胞增殖和存活的影响受HER2状态影响，为探索使用AKT抑制剂进行ARID1A缺陷/HER2阴性GC的靶向治疗提供了理论基础。 © 2023。作者可独家许可国际胃癌协会和日本胃癌协会。

The PI3K/AKT signaling pathway is frequently activated in gastric cancer (GC); however, AKT inhibitors are not effective in unselected GC patients in clinical trials. Mutations in AT-rich interactive domain 1A (ARID1A), which are found in approximately 30% of GC patients, activate PI3K/AKT signaling, suggesting that targeting the ARID1A deficiency-activated PI3K/AKT pathway is a therapeutic candidate for ARID1A-deficient GC.The effect of AKT inhibitors was evaluated using cell viability and colony formation assays in ARID1A-deficient and ARID1A knockdown ARID1A-WT GC cells as well as in HER2-positive and HER2-negative GC. The Cancer Genome Atlas cBioPortal and Gene Expression Omnibus microarray databases were accessed to determine the extent of dependence of GC cell growth on the PI3K/AKT signaling pathway.AKT inhibitors decreased the viability of ARID1A-deficient cells and the inhibitory effect was greater in ARID1A-deficient/HER2-negative GC cells. Bioinformatics data suggested that PI3K/AKT signaling plays a greater role in proliferation and survival in ARID1A-deficient/HER2-negative GC cells than in ARID1A-deficient/HER2-positive cells, supporting the higher therapeutic efficacy of AKT inhibitors.The effect of AKT inhibitors on cell proliferation and survival is affected by HER2 status, providing a rationale for exploring targeted therapy using AKT inhibitors in ARID1A-deficient/HER2-negative GC.© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.