The akt inhibitor azd5363 elicits synthetic lethality in arid1a-deficient gastric cancer cells via induction of pyroptosis

ABSTRACT BACKGROUND Gastric cancer (GC) is a deadly disease with poor overall survival and limited therapeutic options. Genetic alterations such as mutations and/or deletions in chromatin

remodeling gene AT-rich interactive domain 1 A (ARID1A) occur frequently in GC. Although ARID1A mutations/deletions are not a druggable target for conventional treatments, novel therapeutic

strategies based on a synthetic lethal approach may be effective for the treatment of ARID1A-deficient cancers. METHODS A kinase inhibitor library containing 551 compounds was screened in

ARID1A isogenic GC cells for the ability to induce synthetic lethality effect. Selected hits’ activity was validated, and the mechanism of the most potent candidate drug, AKT inhibitor

AD5363 (capivasertib), on induction of the synthetic lethality with ARID1A deficiency was investigated. RESULTS After robust vulnerability screening of 551 diverse protein kinase inhibitors,

we identified the AKT inhibitor AZD5363 as being the most potent lead compound in inhibiting viability of ARID1A−/− cells. A synthetic lethality between loss of ARID1A expression and AKT

inhibition by AZD5363 was validated in both GC cell model system and xenograft model. Mechanistically, AZD5363 treatment induced pyroptotic cell death in ARID1A-deficient GC cells through

activation of the Caspase-3/GSDME pathway. Furthermore, ARID1A occupied the AKT gene promoter and regulated its transcription negatively, thus the GC cells deficient in ARID1A showed

increased expression and phosphorylation of AKT. CONCLUSIONS Our study demonstrates a novel synthetic lethality interaction and unique mechanism between ARID1A loss and AKT inhibition, which

may provide a therapeutic and mechanistic rationale for targeted therapy on patients with ARID1A-defective GC who are most likely to be beneficial to AZD5363 treatment. Access through your

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BEING VIEWED BY OTHERS THERAPEUTIC TARGETING OF ARID1A-DEFICIENT CANCER CELLS WITH RITA (REACTIVATING P53 AND INDUCING TUMOR APOPTOSIS) Article Open access 29 May 2024 BRD4 INHIBITION

INDUCES SYNTHETIC LETHALITY IN _ARID2_-DEFICIENT HEPATOCELLULAR CARCINOMA BY INCREASING DNA DAMAGE Article 11 January 2022 TARGETING USP8 CAUSES SYNTHETIC LETHALITY THROUGH DEGRADATION OF

FGFR2 IN ARID1A-DEFICIENT OVARIAN CLEAR CELL CARCINOMA Article Open access 12 March 2025 DATA AVAILABILITY The authors agree to make the data in this paper publicly available on genuine

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occupancy by SWI/SNF. Mol Cell Biol. 2013;33:265–80. Article  CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS We would like to acknowledge the central

animal facility at Fujian Medical University for the help with animal experiments. We sincerely thank the technical support from Junjin Lin and Shuping Zheng (Public Technology Service

Center, Fujian Medical University) for assistance with flow cytometry and confocal microscopy experiments. FUNDING This work was supported in part by a grant from the National Natural

Science Foundation of China (81672967), the Startup Fund for High-Level Talents of Fujian Medical University (XRCZX2017021), and the Startup Fund for Scientific Research of Fujian Medical

University (No. 2019QH2003). AUTHOR INFORMATION Author notes * These authors contributed equally: Menghan Fang, Youfen Lin. AUTHORS AND AFFILIATIONS * Key Laboratory of Gastrointestinal

Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China Menghan Fang, Youfen Lin, Chaorong Xue, Kaiqin Sheng, Zegeng Guo, Yuting Han, Hanbin Lin, Yuecheng Wu, Xu Lin & 

Xinjian Lin * Department of Endocrinology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China Youfen Lin * Scientific Research Center, Anxi County Hospital, Quanzhou,

China Yuchao Sang, Xintan Chen & Xinjian Lin * Department of Medicine and the Moores Cancer Center, University of California, San Diego, CA, USA Stephen B. Howell * Fujian Key Laboratory

of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China Xu Lin Authors * Menghan Fang View author publications You can also search for this

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search for this author inPubMed Google Scholar * Yuting Han View author publications You can also search for this author inPubMed Google Scholar * Hanbin Lin View author publications You

can also search for this author inPubMed Google Scholar * Yuecheng Wu View author publications You can also search for this author inPubMed Google Scholar * Yuchao Sang View author

publications You can also search for this author inPubMed Google Scholar * Xintan Chen View author publications You can also search for this author inPubMed Google Scholar * Stephen B.

Howell View author publications You can also search for this author inPubMed Google Scholar * Xu Lin View author publications You can also search for this author inPubMed Google Scholar *

Xinjian Lin View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS MHF and YFL designed and performed experiments, analyzed data and wrote the

manuscript. CRX, KQS, ZGG, YTH, HBL, YCW, and YCS performed the experiments and analyzed data. SBH and XTC contributed to data interpretation and editing the paper. XL and XJL designed

experiments, supervised the study, wrote and edit the manuscript. CORRESPONDING AUTHORS Correspondence to Xu Lin or Xinjian Lin. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare

no competing interests. ETHICS APPROVAL AND CONSENT TO PARTICIPATE This article does not contain any studies with human participants. All procedures were carried out according to the Animal

Care and Use Committee protocol approved for this study by Fujian Medical University (FMU-IACUC 15–066) and performed in accordance with the institution guidelines. ADDITIONAL INFORMATION

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law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Fang, M., Lin, Y., Xue, C. _et al._ The AKT inhibitor AZD5363 elicits synthetic lethality in ARID1A-deficient gastric

cancer cells via induction of pyroptosis. _Br J Cancer_ 131, 1080–1091 (2024). https://doi.org/10.1038/s41416-024-02778-5 Download citation * Received: 03 July 2023 * Revised: 11 June 2024 *

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