RRC ID 78647
Author Sato T, Saito M, Nakajima S, Saito K, Katagata M, Fukai S, Okayama H, Sakamoto W, Saze Z, Momma T, Mimura K, Kono K.
Title ARID1A deficiency is targetable by AKT inhibitors in HER2-negative gastric cancer.
Journal Gastric Cancer
Abstract 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.
Volume 26(3)
Pages 379-392
Published 2023-5-1
DOI 10.1007/s10120-023-01373-6
PII 10.1007/s10120-023-01373-6
PMID 36811690
MeSH Cell Line, Tumor DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Humans Phosphatidylinositol 3-Kinases / genetics Phosphatidylinositol 3-Kinases / metabolism Protein Kinase Inhibitors / pharmacology Proto-Oncogene Proteins c-akt / metabolism Signal Transduction Stomach Neoplasms* / drug therapy Stomach Neoplasms* / genetics Stomach Neoplasms* / metabolism Transcription Factors* / metabolism
Human and Animal Cells NUGC-4(RCB1939) MKN7(RCB0999) MKN45(RCB1001)