ARID1A deficiency is targetable by AKT inhibitors in HER2-negative gastric cancer
ARID1A deficiency is targetable by AKT inhibitors in HER2-negative gastric cancer
复制标题
AKT 抑制剂可靶向治疗 HER2 阴性胃癌中的 ARID1A 缺陷
DOI：
10.1007/s10120-023-01373-6
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发表时间：
2023
期刊：
影响因子：
7.4
通讯作者：
Kono Koji
中科院分区：
文献类型：
--
作者：
Sato Takahiro;Saito Motonobu;Nakajima Shotaro;Saito Katsuharu;Katagata Masanori;Fukai Satoshi;Okayama Hirokazu;Sakamoto Wataru;Saze Zenichiro;Momma Tomoyuki;Mimura Kosaku;Kono Koji
研究背景PI 3 K/AKT信号通路在胃癌中被频繁激活，而AKT抑制剂对胃癌患者的临床疗效不佳。在大约30%的GC患者中发现的富含AT的相互作用结构域1A（ARID 1A）中的突变激活PI 3 K/AKT信号传导，提示靶向ARID 1A缺陷激活的PI 3 K/AKT通路是ARID 1A缺陷型GC的治疗候选物。WT GC细胞以及HER 2阳性和HER 2阴性GC中。访问癌症基因组图谱cBioPortal和基因表达Omnibus微阵列数据库，以确定GC细胞生长对PI 3 K/AKT信号通路的依赖程度。结果AKT抑制剂降低了ARID 1A缺陷细胞的生存能力，抑制作用在ARID 1A缺陷/HER 2阴性GC细胞中更大。生物信息学数据表明，PI 3 K/AKT信号传导在ARID 1A缺陷/HER 2阴性GC细胞中的增殖和存活中比在ARID 1A缺陷/HER 2阳性细胞中起更大的作用，支持AKT抑制剂的更高治疗功效。为探索在ARID 1A缺陷/HER 2阴性GC中使用AKT抑制剂的靶向治疗提供了理论基础。
BackgroundThe 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.MethodsThe effect of AKT inhibitors was evaluated using cell viability and colony formation assays in ARID1A-deficient andARID1AknockdownARID1A-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.ResultsAKT 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.ConclusionsThe 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.