RT Journal Article
SR Electronic
T1 Loss of ARID1A activates mTOR signaling and SOX9 in gastric adenocarcinoma—rationale for targeting <em>ARID1A</em> deficiency
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 467
OP 478
DO 10.1136/gutjnl-2020-322660
VO 71
IS 3
A1 Xiaochuan Dong
A1 Shumei Song
A1 Yuan Li
A1 Yibo Fan
A1 Lulu Wang
A1 Ruiping Wang
A1 Longfei Huo
A1 Ailing Scott
A1 Yan Xu
A1 Melissa Pool Pizzi
A1 Lang Ma
A1 Ying Wang
A1 Jiangkang Jin
A1 Wei Zhao
A1 Xiaodan Yao
A1 Randy L Johnson
A1 Linghua Wang
A1 Zhenning Wang
A1 Guang Peng
A1 Jaffer A Ajani
YR 2022
UL http://gut.bmj.com/content/71/3/467.abstract
AB Background Gastric adenocarcinoma (GAC) is a lethal disease with limited therapeutic options. Genetic alterations in chromatin remodelling gene AT-rich interactive domain 1A (ARID1A) and mTOR pathway activation occur frequently in GAC. Targeting the mechanistic target of rapamycin (mTOR) pathway in unselected patients has failed to show survival benefit. A deeper understanding of GAC might identify a subset that can benefit from mTOR inhibition.Methods Genomic alterations in ARID1A were analysed in GAC. Mouse gastric epithelial cells from CK19-Cre-Arid1Afl/fl and wild-type mice were used to determine the activation of oncogenic genes due to loss of Arid1A. Functional studies were performed to determine the significance of loss of ARID1A and the sensitivity of ARID1A-deficient cancer cells to mTOR inhibition in GAC.Results More than 30% of GAC cases had alterations (mutations or deletions) of ARID1A and ARID1A expression was negatively associated with phosphorylation of S6 and SOX9 in GAC tissues and patient-derived xenografts (PDXs). Activation of mTOR signalling (increased pS6) and SOX9 nuclear expression were strongly increased in Arid1A−/− mouse gastric tissues which could be curtailed by RAD001, an mTOR inhibitor. Knockdown of ARID1A in GAC cell lines increased pS6 and nuclear SOX9 and increased sensitivity to an mTOR inhibitor which was further amplified by its combination with fluorouracil both in vitro and in vivo in PDXs.Conclusions The loss of ARID1A activates pS6 and SOX9 in GAC, which can be effectively targeted by an mTOR inhibitor. Therefore, our studies suggest a new therapeutic strategy of clinically targeting the mTOR pathway in patients with GAC with ARID1A deficiency.Data are available upon reasonable request.