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

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.