4.6 Article

ARID1A deficiency is targetable by AKT inhibitors in HER2-negative gastric cancer

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GASTRIC CANCER
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SPRINGER
DOI: 10.1007/s10120-023-01373-6

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ARID1A; HER2; AKT inhibitor; PI3K; AKT signaling pathway; Gastric cancer

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Background: The PI3K/AKT signaling pathway is frequently activated in gastric cancer (GC), but AKT inhibitors are not effective in unselected GC patients. Methods: The effect of AKT inhibitors on cell viability was evaluated in ARID1A-deficient and ARID1A knockdown GC cells, as well as in HER2-positive and HER2-negative GC. Results: AKT inhibitors decreased the viability of ARID1A-deficient cells, with a greater effect in ARID1A-deficient/HER2-negative GC cells. Conclusion: AKT inhibitors show higher therapeutic efficacy in ARID1A-deficient/HER2-negative GC cells, suggesting targeted therapy using AKT inhibitors as a potential treatment strategy.
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 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.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.

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