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Translational Therapeutics

The AKT inhibitor AZD5363 elicits synthetic lethality in ARID1A-deficient gastric cancer cells via induction of pyroptosis

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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.

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Fig. 1: Generation of ARID1A-knockout GC cells and screening of protein kinase inhibitor library for synthetic lethality.
Fig. 2: In vitro and in vivo synthetic lethality in ARID1A-KO GC cells by AKT inhibition.
Fig. 3: AZD5363 induces pyroptosis in ARID1A deficient cells.
Fig. 4: The pyroptosis induced by AZD5363 is mediated through caspase-3/GSDME pathway.
Fig. 5: ARID1A functions as AKT transcriptional repressor.
Fig. 6: A proposed model of the synthetic lethality between ARID1A loss and AKT inhibition.

Data availability

The authors agree to make the data in this paper publicly available on genuine request.

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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 Jun** Lin and Shu** 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).

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Author notes

  1. These authors contributed equally: Menghan Fang, Youfen Lin.

Authors and Affiliations

  1. 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 & **njian Lin

  2. Department of Endocrinology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China

    Youfen Lin

  3. Scientific Research Center, Anxi County Hospital, Quanzhou, China

    Yuchao Sang, **ntan Chen & **njian Lin

  4. Department of Medicine and the Moores Cancer Center, University of California, San Diego, CA, USA

    Stephen B. Howell

  5. Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China

    Xu Lin

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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 **njian Lin.

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The authors declare no competing interests.

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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.

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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 (2024). https://doi.org/10.1038/s41416-024-02778-5

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