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.
- gastric cancer
- gastric neoplasia
- gastrointestinal cancer
- gene expression
Data availability statement
Data are available upon reasonable request.
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Contributors Conception and design: SS and JAA. Development of methodology: XD, SS, LH, YF, JJ and YL. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc): XD, YL, YF, YX, JJ, AS, WZ, LM, LW, XY, MPP and SS. Analysis and interpretation of data (eg, statistical analysis, biostatistics, computational analysis): SS, RW and LW. Writing, review, and/or revision of the manuscript: XD, SS, LH and JAA. Administrative, technical, or material support (ie, reporting or organising data, constructing databases): SS, XD, GP and RLJ. Study supervision: SS. Other (financial support): JAA and SS.
Funding This work was supported by Public Health Service Grant DF56338, which supports the Texas Medical Center Digestive Diseases Center (SS); The University of Texas MD Anderson Cancer Center Institutional Research Grant (3-0026317, SS); U.S. Department of Defense grants CA160433, CA170906(SS); and and National Institutes of Health/National Cancer Institute grants CA129906, CA138671, and CA172741 (JAA). This work was also supported by the NIH/NCI under award number P30CA016672 and under award number P30CA016672 for MDACC core facilities.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Please add Dr. Jaffer A Ajani's ORCID ID: 0000-0001-9946-0629; and adding: Dr. Guang Peng's ORCID ID: 0000-0002-4392-1497 thanks.
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