The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR
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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“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 Reaper et al., 2011
Citations
Cites
The DNA-damage response in human biology and disease
Jackson, S. P., & Bartek, J. (2009) · Nature · doi:10.1038/nature08467 · Cited by 6,092
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
Bakkenist, C. J., & Kastan, M. B. (2003) · Nature · doi:10.1038/nature01368 · Cited by 3,466
Patterns of somatic mutation in human cancer genomes
Greenman, C. D., Stephens, P., Smith, R., Dalgliesh, G. L., Hunter, C., Bignell, G. R., Davies, H. R., Teague, J. W., Butler, A. P., Stevens, C., et al. (2007) · Nature · doi:10.1038/nature05610 · Cited by 3,062
Somatic mutations affect key pathways in lung adenocarcinoma
Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B., et al. (2008) · Nature · doi:10.1038/nature07423 · Cited by 2,681
An Oncogene-Induced DNA Damage Model for Cancer Development
Halazonetis, T. D., Gorgoulis, V. G., & Bartek, J. (2008) · Science · doi:10.1126/science.1140735 · Cited by 1,851
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
Kinner, A., Wu, W., Staudt, C., & Iliakis, G. E. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn550 · Cited by 1,303
Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress
Ward, I. M., & Chen, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.c100569200 · Cited by 1,150
ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks
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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Items 601–641 of 641
Casimir, L., Zimmer, S., Racine-Brassard, F., Goudreau, F., Jacques, P., & Maréchal, A. (2023) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2023.111834 · Cited by 1
Guo, Y., Wang, J., Benedict, B., Chen, Y., van Gemert, F. P. A., Ma, X., Gao, D., Wang, H., Zhang, S., Lieftink, C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16829569
Guo, Y., Wang, J., Benedict, B., Chen, Y., van Gemert, F. P. A., Ma, X., Gao, D., Wang, H., Zhang, S., Lieftink, C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16829560
Therapeutic Targeting of ATR in Cancer
Haciefendi, A., & Eskiler, G. G. (2024) · Interdisciplinary cancer research · doi:10.1007/16833_2024_318
Cell cycle checkpoint activity in the malaria parasite Plasmodium falciparumPreprint
Johnson, M. K., Naldoni, J., Lewis, W. H., Waller, R. F., & Merrick, C. J. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.08.652832
Biomarker-directed therapy for pancreatic cancer
Pishvaian, M. J., & Brody, J. R. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-800684-9.00001-0
DDR kinase inhibition causes hypersensitivity to Taxol through caspase-3 activation
Zaiger, M., Maëda, J., Murakami, M., & Kato, T. A. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152556
Hybrid Molecules of p53 Activators and Protoflavones to Target Multiple Myeloma
Lopes, F., Girst, G., Rincón, R., Ferreira, R. J. F., Gonçalves, L., Saraiva, L., Wang, H., Cuendet, M., Hunyadi, A., & Santos, M. M. M. (2025) · ChemMedChem · doi:10.1002/cmdc.202500600
Context-aware gene dependency modeling via graph attention networks for precision oncology
Yu, G., Gong, Y., Fan, B., Gao, J., & Fan, Q. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07501-3 · Cited by 2
“…screens have facilitated the discovery of context-specific vulnerabilities, such as enhanced sensitivity to ATR inhibitors in ATM-deficient models [13] Other efforts have uncovered targets like WRN helicase in microsatellite instability (MSI) tumors [14], or PARP sensitivity in CDK12-defi-cient…”
Targeting synthetic lethality: an effective therapeutic approach in ovarian and endometrial cancers
Lebeau, A., Kakkos, A., Leroi, N., Bours, V., Delbecque, K., Goffin, F., Gonne, E., & Gennigens, C. (2025) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359251392106
Prpf4 sequentially regulates the expansion and maturation of erythrocyte through distinct mechanisms
Deng, Z., Huang, S., Pei, Y., Li, H., Dong, Y., Li, Y., Ran, Q., Liu, X., Feng, Y., Wang, Q., et al. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02846-6
Pannhausen, J., Chughtai, A. A., Yüce, C.-L., Melzer, M. K., Ma, Y., Seillier, L., van der Vorst, E. P. C., Andrieux, G., Wirtz, J., Leypold, S., et al. (2025) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03603-4 · Cited by 1
“Mechanistically, our data support that ATR inhibition exploits a synthetic-lethal interaction in tumors with p53 loss, a common event in BLCA [1, 115, 116].”
Wei, W., Shi, F., Xu, Y., Jiao, Y., Zhang, Y., Ou, Q., Wu, X., Yang, L., & Lai, J. (2024) · Figshare · doi:10.6084/m9.figshare.26648265
Guo, Y., Wang, J., Benedict, B., Yang, C., van Gemert, F., Ma, X., Gao, D., Wang, H., Zhang, S., Lieftink, C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16829572
Guo, Y., Wang, J., Benedict, B., Yang, C., van Gemert, F., Ma, X., Gao, D., Wang, H., Zhang, S., Lieftink, C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16829566
Zhou, X. H., Qin, Q., Yao, H., Fu, Y., Wang, L., Zhu, W., & Lv, Q. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.109538 · Cited by 2
Badakul, G., Maëda, J., & Kato, T. A. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1776137
3-D Genome organization of DNA damage repair
Banerjee, U. K. (2017) · theses.fr (ABES) · doi:10.70675/25480b49zc194z4a4bzb6b0z2f84dab6ccef
Cristini, A. (2015) · theses.fr (ABES) · doi:10.70675/89719cadza51cz4509zbd9fz3da99c280491
Mutations de la voie ATR-CHK1, réponse au stress réplicatif et cancer
Egger, T. (2018) · theses.fr (ABES) · doi:10.70675/eb51eb1ezc51dz4737zaf38z954d1a68dbea
Epigenomic and 3D-genomic changes in Mantle Cell Lymphoma
Karpukhina, A. A. (2024) · theses.fr (ABES) · doi:10.70675/07b193edz7113z43b1z8a89zf8e13bc9f359
Chailapakul, P., Maëda, J., Miura, T., & Kato, T. A. (2026) · Mutagenesis · doi:10.1093/mutage/geag018
“ATM inhibitor (KU55933) [ 18], ATR inhibitor (VE-821) [ 19], DNA-PK inhibitor (NU7441), and PARP inhibitor (NU1025) were acquired from Selleck Chemicals.”
Alfayomy, A. M., Neuroth, S., Sarnow, A., Handke, L., Robaa, D., Erdmann, F., Decroos, C., Schmidt, M., Romier, C., Schutkowski, M., et al. (2026) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2026.119125
Cell cycle checkpoint activity in the malaria parasite Plasmodium falciparum
Johnson, M. K., Naldoni, J., Lewis, W. H., Waller, R. F., & Merrick, C. J. (2026) · mSphere · doi:10.1128/msphere.00341-26 · Cited by 1
Cheng, H., Chen, Y., Liu, P.-Y., Jin, X., Qu, Y., Liu, B., & Ai-zhuo, L. (2026) · Acta Pharmacologica Sinica · doi:10.1038/s41401-026-01892-9 · Cited by 1
Awwad, S. W., Barber, H., Coulthard, J., Lam, S. C. C., Rojas, A., Gueorguieva, N., Woods, M., Balmus, G., Belotserkovskaya, R., & Jackson, S. P. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag811
“ATRi are being explored predominantly as therapies for subsets of cancers that either experience high replication stress or have lost the related kinase, ATM [ 14–19 ].”
Synthetic lethality in cancer: mechanisms, therapeutic exploitation and clinical translation
Camps-Fajol, C., Minguillón, J., & Surrallés, J. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02954-4 · Cited by 1
“338 Besides, based on the described SL mechanism between ATM and ATR, a Phase II trial in epithelial ovarian cancer (NCT06433219) and a Phase I in solid tumors (NCT05396833) combining lartesertib with the ATRi tuvusertib are ongoing.”
InfluentialLiu, S., & Sun, C. (2026) · Cancer and Metastasis Reviews · doi:10.1007/s10555-026-10385-4
“Preclinical studies have shown that ATR inhibitors selectively kill ATM-or p53-deficient cancer cells [89], and clinical trials exploring synthetic lethality in HGSOC via ATM-CHK2-p53 pathway disruption have consequently focused on targeting the G2/M checkpoint with ATR, CHK1, or WEE1 inhibitors,…”
BindingDB (2013) · UC San Diego · doi:10.7270/q23j3f2g
BindingDB Entry 50045098: Development of synthetic lethality anticancer therapeutics.
BindingDB (2016) · UC San Diego · doi:10.7270/q2vd714c
BindingDB (2021) · UC San Diego · doi:10.7270/q2bz69c9
BindingDB (2017) · UC San Diego · doi:10.7270/q26975h1
BindingDB (2021) · UC San Diego · doi:10.7270/q29c71zt
Metadata
- 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
- Venue
- Nature Chemical Biology
- Published
- 2011-04-13
- Volume
- 7
- Issue
- 7
- Pages
- 428-430
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- 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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