Cited by 641DNA Repair MechanismsPARP inhibition in cancer therapyCancer-related Molecular Pathways

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Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR

Reaper, Philip M, Griffiths, Matthew R, Long, Joanna M, Charrier, Jean-Damien, MacCormick, Somhairle, Charlton, Peter A, Golec, Julian M C, Pollard, John R·2011·Nature Chemical Biology

DOI 10.1038/nchembio.573

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Abstract

Here we report a comprehensive biological characterization of a potent and selective small-molecule inhibitor of the DNA damage response (DDR) kinase ATR. We show a profound synthetic lethal interaction between ATR and the ATM-p53 tumor suppressor pathway in cells treated with DNA-damaging agents and establish ATR inhibition as a way to transform the outcome for patients with cancer treated with ionizing radiation or genotoxic drugs.

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ATR: an essential regulator of genome integrity
Cimprich, K. A., & Cortez, D. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2450 · Cited by 1,798
DNA Repair by ERCC1 in Non–Small-Cell Lung Cancer and Cisplatin-Based Adjuvant Chemotherapy
Olaussen, K. A., Dunant, A., Fouret, P. J., Brambilla, E. M., André, F., Haddad, V., Clermont, E., Filipits, M., Pirker, R., Popper, H., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa060570 · Cited by 1,725
-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin
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Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress
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Jazayeri, A., Falck, J., Lukas, C., Bartek, J., Smith, G. C. M., Lukas, J., & Jackson, S. P. (2006) · Nature Cell Biology · doi:10.1038/ncb1337 · Cited by 1,064

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“Compound 67was shown to be a potent ATP-competitive inhibitor of ATR (Ki 1⁄4 13 nM) with good selectivity over a panel of the related PIKKs, ATM, DNA-PKcs and mTOR [106].”
BackgroundInfluential
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“Almost simultaneously, another study shows that inhibition of ATR kinase by selective ATR inhibitor VE-821 (IC50 = 26 nM) in ATM pathway defected tumor cell HCT116 markedly sensitizes cyto-toxicity of cisplatin by tenfolds, while almost no sensitization effect was observed in normal cells (Reaper et al., 2011).”
Background
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“For example, inhibition of ATR, which is a backup kinase of ATM, has been reported to be particularly effective in tumors with TP53 or ATM mutations [58].”
Background
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“…time points and analyzing a broader range of proteins involved in DNA damage repair pathways, such as Ataxia telangiectasia-mutated (ATM), Ataxia telangiectasia and Rad3-related protein (ATR), and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) [46, 47], through Western blot experiments.”
Targeting of the cellular ATM rather than ATR kinase exhibits therapeutic potential during the lumpy skin disease virus infection in vivo and in vitro
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“3,4 Mutations in TP53 and other DDR genes, including BRCA1 33–35 In a phase 2 trial, the combination of berzosertib and gemcitabine improved PFS in recurrent platinum - resistant high - grade serous ovarian carcinoma (HGSOC) compared with gemcitabine alone.”
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“In preclinical models, combining ATR inhibition with DNA-damaging drugs dramatically increases tumor cell mortality [233,234].”
Auranofin attenuates TOPBP1-mediated ATR replication stress response and improves chemotherapeutic response in breast tumor models
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“When combined with specific DDR inhibitors, such as SCH900776 (a CHK1 inhibitor) (Guzi et al., 2011), VE-821 (an ATR inhibitor) (Reaper et al., 2011), and olaparib (a PARP-1 inhibitor) (Fo et al., 2009), we assessed the synergistic potential of the most potent topoisomerase-targeting derivatives…”
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“…WEE1 was identified as selective lethal in H3K36me3-deficient cancers 243 , ATR as a selective lethal target in ATM -, TP53 - or ARID1A -mutant cancers 244,245 , and PKMYT1 as a synthetic lethality associated with CCNE1 amplification 246 , but each is pan-lethal in large-scale datasets 22 .”
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Background
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“Such effect could be caused by a defective ATM-p53 pathway (Reaper et al., 2011).”
Background
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Background
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“32,33 Transcriptomic analysis showed that TP53 status did not impact ATR expression in HMCLs, isogenic myeloma clones, or patient samples (Figure 5A –”
Background
Efficacy of ATR Kinase Inhibitor Elimusertib Monotherapy or Combination in Tumors with DNA Damage Response Pathway and Other Genomic Alterations
Varadarajan, K., Pico, C. X. C., Evans, K. W., Raso, M. G., Rizvi, Y. Q., Zheng, X., Chachad, D., DiPeri, T. P., Wang, B., Scott, S. M., et al. (2025) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-24-0884 · Cited by 1
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“through inhibition can result in synthetic lethality [36].”
Background
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Background
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Authors: Reaper, P. M., Griffiths, M. R., Long, J. M., Charrier, J.-D., MacCormick, S., Charlton, P. A., Golec, J. M. C., & Pollard, J. R.
Affiliations: Vertex Pharmaceuticals (United Kingdom) (GB)
Corresponding author: Pollard, John R
ORCID: MacCormick, Somhairle
Pollard, John R
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2011-04-13
Volume: 7
Issue: 7
Pages: 428-430
ISSN: 1552-4450 (ISSN-L)
1552-4469
DOI: 10.1038/nchembio.573
OpenAlex: W2022529631
Cited by: 633
References: 25
Citations by year: 2026: 21 · 2025: 41 · 2024: 34 · 2023: 41 · 2022: 41 · 2021: 46 · 2020: 51 · 2019: 39 · 2018: 51 · 2017: 53 · 2016: 56 · 2015: 51 · 2014: 41 · 2013: 38 · 2012: 22
FWCI: 14.17
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Chemical Biology (publishedVersion)
PubMed (publishedVersion)
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, ATM, p53, DNA damage response, radiosensitivity, DNA-damaging agents, small-molecule kinase inhibitors, tumor cell killing, tumor suppressor pathways
MeSH terms: Animals, Antineoplastic Agents, DNA Damage, DNA-Binding Proteins, Dose-Response Relationship, Drug, Fibroblasts, Humans, Pyrazines, Sulfones, Molecular Structure, Tumor Suppressor Protein p53, Cell Death, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Cell Line, Tumor, Cell Proliferation, Ataxia Telangiectasia Mutated Proteins

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Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR

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