ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A
Open accessAbstract
Identifying genetic biomarkers of synthetic lethal drug sensitivity effects provides one approach to the development of targeted cancer therapies. Mutations in ARID1A represent one of the most common molecular alterations in human cancer, but therapeutic approaches that target these defects are not yet clinically available. We demonstrate that defects in ARID1A sensitize tumour cells to clinical inhibitors of the DNA damage checkpoint kinase, ATR, both in vitro and in vivo . Mechanistically, ARID1A deficiency results in topoisomerase 2A and cell cycle defects, which cause an increased reliance on ATR checkpoint activity. In ARID1A mutant tumour cells, inhibition of ATR triggers premature mitotic entry, genomic instability and apoptosis. The data presented here provide the pre-clinical and mechanistic rationale for assessing ARID1A defects as a biomarker of single-agent ATR inhibitor response and represents a novel synthetic lethal approach to targeting tumour cells.
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Drug screening with organoids can provide connections between genetic mutations and drug responses.
“Since organoids can maintain the genomic profile of the parent tissue158, drug screening can be used to provide connections between genetic mutations and drug responses37,154,159.”
From Organoids (2022) · cites this paper as [159]
The Results section (“RNAi screens identify ARID1A as ATRi synthetic lethal partner”; page unavailable) describes screening for genetic determinants of ATR-inhibitor response, supporting the general link between genetic changes and drug response. But the screening used cell lines, not organoids, so this paper does not establish the organoid-specific part of the claim. (LLM, conf=0.86)
Experimental — accuracy not yet measuredYan and colleagues showed that gastric cancer organoids with ARID1A mutations were sensitive to ATR inhibitors, supporting a previous study and identifying an intervention for a class of mutations considered undruggable.
“By screening gastric cancer organoids from seven patients against 37 drugs, Yan and colleagues showed that tumors with ARID1A mutations were sensitive to ATR inhibitors159, supporting a previous study160 and functionally identifying an intervention for a class of mutations that were considered undruggable.”
From Organoids (2022) · cites this paper as [159]
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Self-citation
- Authors
- Williamson, C. T., Miller, R., Pemberton, H. N., Jones, S. E., Campbell, J., Konde, A., Badham, N., Rafiq, R., Brough, R., Gulati, A., Ryan, C. J., Francis, J., Vermulen, P. B., Reynolds, A. R., Reaper, P. M., Pollard, J. R., Ashworth, A., & Lord, C. J.
- Affiliations
- Institute of Cancer Research (GB)
- University College Dublin (IE)
- Vertex Pharmaceuticals (United Kingdom) (GB)
- Corresponding author
- Ashworth, Alan
- Lord, Christopher J.
- ORCID
- Venue
- Nature Communications
- Published
- 2016-12-13
- Volume
- 7
- Issue
- 1
- Pages
- 13837-13837
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5159945
- OpenAlex
- W2563490856
- Cited by
- 382
- References
- 48
- Citations by year
- 2026: 23 · 2025: 49 · 2024: 37 · 2023: 49 · 2022: 43 · 2021: 42 · 2020: 51 · 2019: 34 · 2018: 31 · 2017: 22
- FWCI
- 15.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Repository UCD (University College Dublin) (submittedVersion, cc-by)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-nd)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Wellcome Trust (103049, 103049/Z/13/Z)
- Health Research Board
- Vertex Pharmaceuticals
- Cancer Research UK (14276, C347/A8363)
- National Institute for Health and Care Research
- Science Foundation Ireland
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- ATR inhibitors, synthetic lethality, ARID1A deficiency, DNA damage checkpoint, genomic instability, apoptosis, cell cycle defects, tumor markers, targeted cancer therapy
- MeSH terms
- Antineoplastic Agents, DNA-Binding Proteins, Humans, Nuclear Proteins, Transcription Factors, Apoptosis, RNA Interference, Cell Line, Tumor, Cell Cycle Checkpoints, Ataxia Telangiectasia Mutated Proteins
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