A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations
Open accessAbstract
Oncogene activation has been shown to generate replication-born DNA damage, also known as replicative stress. The primary responder to replicative stress is not Ataxia-Telangiectasia Mutated (ATM) but rather the kinase ATM and Rad3-related (ATR). One limitation for the study of ATR is the lack of potent inhibitors. We here describe a cell-based screening strategy that has allowed us to identify compounds with ATR inhibitory activity in the nanomolar range. Pharmacological inhibition of ATR generates replicative stress, leading to chromosomal breakage in the presence of conditions that stall replication forks. Moreover, ATR inhibition is particularly toxic for p53-deficient cells, this toxicity being exacerbated by replicative stress-generating conditions such as the overexpression of cyclin E. Notably, one of the compounds we identified is NVP-BEZ235, a dual phosphatidylinositol-3-OH kinase (PI3K) and mTOR inhibitor that is being tested for cancer chemotherapy but that we now show is also very potent against ATM, ATR and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs).
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An association of TP53-deficiency and sensitivity to ATR inhibitors has been described as profound synthetic lethality.
“an association of TP53-deficiency and sensitivity to ATR inhibitors has been described as profound synthetic lethality (Reaper et al., 2011;Toledo et al., 2011)”
From Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer (2021) · cites this paper as Toledo et al., 2011
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- Authors
- Toledo, L. I., Murga, M., Zur, R., Soria, R., Rodriguez, A., Martinez, S., Oyarzabal, J., Pastor, J., Bischoff, J. R., & Fernandez-Capetillo, O.
- Affiliations
- Spanish National Cancer Research Centre (ES)
- Venue
- Nature Structural & Molecular Biology
- Published
- 2011-05-08
- Volume
- 18
- Issue
- 6
- Pages
- 721-727
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC4869831
- OpenAlex
- W2065434335
- Cited by
- 465
- References
- 51
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 18 · 2023: 25 · 2022: 20 · 2021: 38 · 2020: 23 · 2019: 29 · 2018: 46 · 2017: 39 · 2016: 38 · 2015: 34 · 2014: 41 · 2013: 44 · 2012: 36
- FWCI
- 17.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- ATR inhibitors, synthetic lethality, p53 deficiency, ATM, DNA-PKcs, NVP-BEZ235, PI3K/mTOR inhibitors, replication fork stalling, chromosome breakage, cyclin E, cell-based screening, cancer chemotherapy
- MeSH terms
- Animals, Antineoplastic Agents, Cell Survival, Cells, Cultured, Drug Screening Assays, Antitumor, Enzyme Inhibitors, Fibroblasts, Imidazoles, Oxazines, Quinolines, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Chromosome Breakage, Mice, Ataxia Telangiectasia Mutated Proteins
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