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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The PI3K/AKT pathway is often activated in gastric cancer (GC), but AKT inhibitors lack efficacy in unselected patients.
• Mutations in AT-rich interactive domain 1A (ARID1A), present in ~30% of GC cases, activate PI3K/AKT signaling.
• Targeting the ARID1A-deficiency-activated PI3K/AKT pathway is a potential therapeutic strategy for ARID1A-deficient GC.

Purpose of the Study:

• To evaluate the efficacy of AKT inhibitors in gastric cancer cells with varying ARID1A and HER2 statuses.
• To determine the role of PI3K/AKT signaling in GC cell growth based on ARID1A and HER2 expression.
• To identify patient subgroups who may benefit from AKT inhibitor therapy.

Main Methods:

• Cell viability and colony formation assays were performed on ARID1A-deficient, ARID1A-knockdown, and wild-type GC cells.
• Experiments included HER2-positive and HER2-negative GC cell lines.
• Bioinformatics analysis of The Cancer Genome Atlas and Gene Expression Omnibus databases assessed PI3K/AKT pathway dependence.

Main Results:

• AKT inhibitors reduced the viability of ARID1A-deficient GC cells.
• The inhibitory effect was more pronounced in ARID1A-deficient/HER2-negative GC cells.
• Bioinformatics data indicated a greater reliance on PI3K/AKT signaling for proliferation and survival in ARID1A-deficient/HER2-negative GC cells.

Conclusions:

• HER2 status influences the efficacy of AKT inhibitors in gastric cancer.
• Targeted therapy with AKT inhibitors is a promising strategy for ARID1A-deficient/HER2-negative GC.
• This finding provides a rationale for clinical trials focusing on this specific GC subtype.