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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The DNA-damage response in human biology and disease
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DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
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ATR: an essential regulator of genome integrity
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DNA Repair by ERCC1 in Non–Small-Cell Lung Cancer and Cisplatin-Based Adjuvant Chemotherapy
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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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A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors
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“Confirming the results in additional cell lines is also important in light of the fact the observed impact of KLF5-KO, albeit statistically significant, appears minimal.”
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“ATR inhibitor has been proved to be hypersensitive to ALT pathway mediated by recombination [68,69].”
Background
ATM Germline-Mutated Gastroesophageal Junction Adenocarcinomas: Clinical Descriptors, Molecular Characteristics, and Potential Therapeutic Implications
Jabbour, T. E., Misyura, M., Cowzer, D., Zimmermann, M., Rimkunas, V. M., Marra, A., Derakhshan, F. N., Selenica, P., Parilla, M., Setton, J. S., et al. (2022) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djac024 · Cited by 13
“Synthetic lethality between loss of function in ATM and ATR inhibition has been reported in preclinical systems, though not specifically in GEJ carcinomas, suggesting that ATM deficiency in GEJ adenocarcinomas may present a targetable vulnerability for ATR inhibitors (30-32).”
ATM regulates Cdt1 stability during the unperturbed S phase to prevent re-replication
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“We also examined possible involvement of ATR in the Cdt1 regulation using an ATR specific kinase inhibitor, VE-821.”
Method
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Radio-sensitizing effects of VE-821 and beyond: Distinct phosphoproteomic and metabolomic changes after ATR inhibition in irradiated MOLT-4 cells
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“TP53-mutant tumours were shown to have increased sensitivity to ATR inhibitors in combination with chemotherapy or radiotherapy [42].”
BackgroundResult
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“ATM is frequently mutated in cancer, and ATM-de ﬁ cient cancer cells are more sensitive to ATRis [34 – 38], probably because of the interdependence between ATM and ATR in response to secondary DSBs induced by RS. Alternatively, combined ATRi and DNA-PKi radiosensitizes tumor cells independently of…”
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“It has been found that wild-type p53 deficient cells are sensitive to ATR inhibition.(10) In addition, ATR is preferentially required for proliferation of p53-deficient human cancer cells.”
Background
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“Treatment of cells with a potent and specific ATR kinase inhibitor, VE-821 [19], prevented the nuclear accumulation of NCK compared to vehicle treatment (Figure 2B).”
BackgroundMethodInfluential
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“While ATR and CHK1 are essential proteins, cancer cells are often deficient in ATM protein and ATM signaling and this renders them sensitive to ATR kinase inhibition [6–9].”
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“Previously, ATR inhibitor was shown to induce ATM activation as a compensatory response (37).”
Background
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Background
Chk’ing p53-deficient breast cancers
Schoppy, D. W., & Brown, E. J. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63205 · Cited by 11
Comparison of the Radiosensitizing Effect of ATR, ATM and DNA-PK Kinase Inhibitors on Cervical Carcinoma Cells
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“When combined with cisplatin, it potentiated inhibition of proliferation but did not induce cell death of normal fibroblasts (Reaper et al., 2011).”
Background
New human ATM variants are able to regain ATM functions in ataxia telangiectasia disease
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“This mechanism has been confirmed by using the ATR kinase inhibitor VE-821 [28, 29].”
Influential
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“6 , 15 , 16 ATR inhibition in ATM-deficient cell lines results in synthetic lethality and renders these tumors more susceptible to DNA-damaging chemotherapies.”
Background
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Background
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Parisi, A., Rossi, F., Filippis, C. D., Paoloni, F., Felicetti, C., Mammarella, A., Pecci, F., Lupi, A., & Berardi, R. (2023) · OncoTargets and Therapy · doi:10.2147/ott.s272563 · Cited by 8
“ATR (Ataxia-telangectasia and Rad3 related) kinase inhibitors sensitize lung cancer cell lines to cisplatin in vitro and in cell line and patient-derived xenografts in vivo: cisplatin and ATR kinase inhibitors have been demonstrated to cooperate in vitro to kill ATM-deficient lung cancer cells and in vivo to resolve A…”
Background
Reevaluation of ATR signaling in primary resting chronic lymphocytic leukemia cells: evidence for pro-survival or pro-apoptotic function
Beyaert, M., Starczewska, E., Gonzalez-Perez, A. C., Vanlangendonck, N., Saussoy, P., Tilman, G., Leener, A. D., Vekemans, M., Neste, E. V. D., & Bontemps, F. (2017) · Oncotarget · doi:10.18632/oncotarget.18144 · Cited by 9
“In line with this, we observed that phosphorylation of H2AX (γH2AX) induced by UV-C in Oncotarget56909www.impactjournals.com/oncotarget CLL cells was completely prevented for up to 60 min by two selective ATR inhibitors, VE-821 and AZ20 [28, 29], used at 10 and 1 μM, respectively (Figure 2B).”
BackgroundInfluential
LC–MS/MS assay for the quantitation of the ATR kinase inhibitor VX-970 in human plasma
Kiesel, B. F., Scemama, J., Parise, R. A., Villaruz, L. C., Iffland, A., Doyle, A., Ivy, P. S., Chu, E., Bakkenist, C. J., & Beumer, J. H. (2017) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2017.08.037 · Cited by 8
“%) and precise (<8.4% CV), and fulfilled criteria from the FDA guidance for bioanalytical method validation.”
MethodInfluential
Identification of subsets of actionable genetic alterations in KRAS-mutant lung cancers using association rule mining
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Chemo-Phosphoproteomic Profiling with ATR Inhibitors Berzosertib and Gartisertib Uncovers New Biomarkers and DNA Damage Response Regulators
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The effect of replication protein A inhibition and post-translational modification on ATR kinase signaling
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“These active site ATRi often have excellent potency in biochemical assays, but less sensitivity in cellular assays, potentially due to the vast difference in the concentration of ATP within both contexts or off target activity towards other kinase active sites 6,7 .”
Background
Epigenetic targeting of PGBD5-dependent DNA damage in SMARCB1-deficient sarcomas
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“Synthetic dependencies in DNA damage signaling, chromatin remodeling, and metabolic functions have recently been defined to develop improved targeted therapies (24– 28).”
A medicinal chemistry perspective on ATR: Current status and future directions
Li, K., Sun, X., Liu, S., Liu, Y., Feng, X., & Zhang, G. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117834 · Cited by 10
The enrichment of Fanconi anemia/homologous recombination pathway aberrations in ATM/ATR-mutated NSCLC was accompanied by unique molecular features and poor prognosis
Wei, W., Shi, F., Xu, Y., Jiao, Y., Zhang, Y., Ou, Q., Wu, X., Yang, L., & Lai, J. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04634-1 · Cited by 7
“For example, loss of ATM in tumors makes tumors more rely on ATR-mediated intra-S and G2/M checkpoints [41], and inhibition of ATR could selectively kill cancer cells with ATM deficiency [7].”
Background
ATM and ATR gene editing mediated by CRISPR/Cas9 in Chinese Hamster cells
Maëda, J., Chailapakul, P., & Kato, T. A. (2024) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2024.111871 · Cited by 7
Chemical inhibition of DNA repair kinases as a promising tool in oncology
Ďurišová, K., Šalovská, B., Pejchal, J., & Tichý, A. (2015) · Biomedical Papers · doi:10.5507/bp.2015.046 · Cited by 7
Up-and-Coming Experimental Drug Options for Metastatic Colorectal Cancer
Cimino, S. K., & Eng, C. (2020) · Journal of Experimental Pharmacology · doi:10.2147/jep.s259287 · Cited by 7
AMOT suppresses tumor progression via regulating DNA damage response signaling in diffuse large B-cell lymphoma
Sang, T., Yang, J., Liu, J., Han, Y., Li, Y., Zhou, X., & Wang, X. (2021) · Cancer Gene Therapy · doi:10.1038/s41417-020-00258-5 · Cited by 7
LC–MS/MS assay for the simultaneous quantitation of the ATM inhibitor AZ31 and the ATR inhibitor AZD6738 in mouse plasma
Kiesel, B. F., Shogan, J. C., Rachid, M., Parise, R. A., Vendetti, F. P., Bakkenist, C. J., & Beumer, J. H. (2017) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2017.01.055 · Cited by 7
Abrogation of ATR function preferentially augments cisplatin-induced cytotoxicity in PTEN-deficient breast cancer cells
Zhao, J., Yang, J., Li, K., Chen, Y., Tang, M., Zhu, H.-L., Nie, C.-I., Yuan, Z., & Zhao, X.-Y. (2023) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2023.110740 · Cited by 6
AZD6738 promotes the tumor suppressive effects of trifluridine in colorectal cancer cells
Harata, S., Suzuki, T., Takahashi, H., Hirokawa, T., Kato, A., Watanabe, K., Yanagita, T., Ushigome, H., Shiga, K., Ogawa, R., et al. (2023) · Oncology Reports · doi:10.3892/or.2023.8489 · Cited by 6
“In the presence of ATR depletion, p53 mutations are lethal (16); however, little is known about the effects of DDR in p53 wild‑type cells (17,18).”
Simultaneous inhibition of ATM, ATR, and DNA-PK causes synergistic lethality
Kato, T. A., Maëda, J., Watanabe, H., Kawamura, S., & Wilson, P. F. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.150517 · Cited by 6
A ROS‐Activatable Agent Elicits Homologous Recombination DNA Repair and Synergizes with Pathway Compounds
Thowfeik, F. S., AbdulSalam, S. F., Wunderlich, M., Wyder, M. A., Greis, K. D., Kadekaro, A. L., Mulloy, J. C., & Merino, E. J. (2015) · ChemBioChem · doi:10.1002/cbic.201500304 · Cited by 6
Chemotherapy and Targeted Agents
Harrington, K. J. (2017) · Elsevier eBooks · doi:10.1016/b978-0-7020-6056-4.00022-8 · Cited by 6
G2/M Checkpoint Abrogation With Selective Inhibitors Results in Increased Chromatid Breaks and Radiosensitization of 82-6 hTERT and RPE Human Cells
Nikolakopoulou, A., Soni, A., Habibi, M., Karaiskos, P., Pantelias, G. E., Terzoudi, G. I., & Iliakis, G. E. (2021) · Frontiers in Public Health · doi:10.3389/fpubh.2021.675095 · Cited by 6
Therapeutic inhibition of ATR in differentiated thyroid cancer
Lin, S., Lee, Y.-Y., Wu, M., Lu, Y., Yeh, C., Chen, W., Chou, T., & Wong, R. J. (2023) · Endocrine Related Cancer · doi:10.1530/erc-23-0142 · Cited by 6
Emerging Subtypes and New Treatments for Castration-Resistant Prostate Cancer
Carneiro, B. A., Lotan, T. L., Souza, A. O., & Aggarwal, R. R. (2020) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_100025 · Cited by 6
The antiproliferative effects of ataxia-telangiectasia mutated and ATM- and Rad3-related inhibitions and their enhancements with the cytotoxicity of DNA damaging agents in cholangiocarcinoma cells
Moolmuang, B., & Ruchirawat, M. (2021) · Journal of Pharmacy and Pharmacology · doi:10.1093/jpp/rgaa050 · Cited by 6
Unpicking the Roles of DNA Damage Protein Kinases in Trypanosomatids
Silva, G. L. A., Tosi, L. R. O., McCulloch, R., & Black, J. A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.636615 · Cited by 7
“, 2018), a selective inhibitor of the ATR kinase in humans (Charrier et al., 2011; Reaper et al., 2011).”
Background
Ataxia telangiectasia mutated (ATM) kinase as a predictive biomarker in clinical oncology: implications for a precision treatment approach
Pham, A. T., Yuan, F., Nagathihalli, N. S., & Dosch, A. R. (2026) · Neoplasia · doi:10.1016/j.neo.2026.101309 · Cited by 5
“Reaper et. al first identified the synthetic lethal interaction between ATR and TP53[93].”
Influential
Targeting ATR in Cancer Medicine
Salguero, C., Valladolid, C., Robinson, H. M. R., Smith, G. C. M., & Yap, T. A. (2023) · Cancer treatment and research · doi:10.1007/978-3-031-30065-3_14 · Cited by 6
Replication stress: an early key event in ochratoxin a genotoxicity?
Klotz, C., Borchers, J., Brode, J., Lambeck, P., & Mally, A. (2025) · Archives of Toxicology · doi:10.1007/s00204-025-04004-4 · Cited by 5
“Hydroxyurea (HU), which results in the accumulation of long ssDNA stretches due to polymerase-helicase uncoupling, was selected as a positive control for ATR signaling (Reaper et al. 2011; Vesela et al. 2017).”
Approaches for Identifying Novel Targets in Precision Medicine: Lessons from DNA Repair
Williams, D. T., & Staples, C. J. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-60733-7_1 · Cited by 6
Lnc956 regulates mouse embryonic stem cell differentiation in response to DNA damage in a p53-independent pathway
Ma, H., Ning, Y., Wang, L., Zhang, W., & Zheng, P. (2023) · Science Advances · doi:10.1126/sciadv.ade9742 · Cited by 5
“To examine whether ATM or ATR signaling regulated the Lnc956-KLF4 association, we inhibited ATM activity with a specific inhibitor KU55933 (35) and ATR activity with VE-821 (36), respectively (fig.”
Method
A DNA-PK phosphorylation site on MET regulates its signaling interface with the DNA damage response
Koch, J. P., Roth, S. M., Quintin, A., Gavini, J., Orlando, E., Riedo, R., Pozzato, C., Hayrapetyan, L., Aebersold, R. H., Stroka, D., et al. (2023) · Oncogene · doi:10.1038/s41388-023-02714-6 · Cited by 5
“At the same time, ATM and ATR inhibition by KU55933 [28] and VE-821 [29] respectively, only had a minor effect (Fig.”
Background
Recent advancement of analytical approaches for assessing Ataxia telangiectasia mutated kinase inhibitors in Ataxia telangiectasia: An overview
Rameshkumar, A., Arunprasanna, V., Mahalakshmi, V. J., Raja, M. R., & Gopinath, K. (2024) · Process Biochemistry · doi:10.1016/j.procbio.2024.05.024 · Cited by 5
Hypoxia and the DNA Damage Response
Olcina, M. M., & Hammond, E. M. (2013) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-1-4614-9167-5_2 · Cited by 5
Novel targets for ATM-deficient malignancies
Winkler, J., Hofmann, K., & Chen, S. (2014) · Molecular & Cellular Oncology · doi:10.4161/mco.29905 · Cited by 5
“2).18 The ATR inhibitor VE821 increases the sensitivity of ATM-defective cells toward cisplatin, the first line treatment for OSCC.18 Previous concerns regarding inhibition of ATR related to the fact that ATR is involved in normal DNA metabolism (e.g., for preventing replication fork collapse) and ATR knockout mice ar…”
BackgroundInfluential
Molecular Taxonomy and Tumourigenesis of Colorectal Cancer
Biswas, S., Holyoake, D., & Maughan, T. (2015) · Clinical Oncology · doi:10.1016/j.clon.2015.11.001 · Cited by 7
Biophysical investigation and conformational analysis of p38α kinase inhibitor doramapimod and its analogues
Nasiri, A. H., Saxena, K., Bats, J. W., Nasiri, H. R., & Schwalbe, H. (2016) · MedChemComm · doi:10.1039/c6md00262e · Cited by 5
Evaluation of [ 18 F]-ATRi as PET tracer for in vivo imaging of ATR in mouse models of brain cancer
Carlucci, G., Carney, B. D., Sadique, A., Vansteene, A., Tang, J., & Reiner, T. (2017) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2017.01.002 · Cited by 5
“These results taken together suggest that replacement of the para proton on the aniline ring with an 18Fatom did not fundamentally perturb the binding properties of [18F]-9 in comparison to Ve-821 (Ve-821: IC50 = 26 nM, [24]) and that Ve-821 and [18F]-9 presumably bind the same target.”
Background
Exploring SPK98 for the Selective Sensitization of ATM- or P53-Deficient Cancer Cells
Priya, B., Dubey, G., & Kirubakaran, S. (2023) · ACS Omega · doi:10.1021/acsomega.2c07356 · Cited by 5
Genetic Variants in DNA Repair Pathways as Potential Biomarkers in Predicting Treatment Outcome of Intraperitoneal Chemotherapy in Patients With Colorectal Peritoneal Metastasis: A Systematic Review
Hulshof, E. C., Lim, L., de Hingh, I. H. J. T., Gelderblom, H. A. J., Guchelaar, H., & Deenen, M. J. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.577968 · Cited by 5
Synthetic Lethality‐Based Targets and Their Exploration in Tumour Combination Strategies
Wu, L., Deng, Y., Lei, Z., Wang, Y., & Huang, S. (2025) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.70756 · Cited by 4
Combination therapy overcomes secondary PARPi resistance in ATM-deficient prostate cancer
Arce‐Gallego, S., Esquefa, V., Domènech, H., Salca, A., Aguilar, D., Casals, T., Arnau, G. M., Simonetti, S., Oliveira, A., de Llobet, L., et al. (2025) · npj Precision Oncology · doi:10.1038/s41698-025-01179-y · Cited by 4
Rb1 deficiency induces synthetic lethality with ATR and PKMYT1 coinhibition in breast cancer cell lines and patient-derived xenografts
Jiang, X., Chen, M.-K., Lee, J. J., Rao, X., Wang, Y., Luo, L., Wang, J., Hunt, K. K., & Keyomarsi, K. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adx6797 · Cited by 5
Kinase Inhibitor-Induced Cell-Type Specific Vacuole Formation in the Absence of Canonical ATG5-Dependent Autophagy Initiation Pathway
Jose, S., Sharma, H., Insan, J., Sharma, K., Arora, V., Puranapanda, S., Dhamija, S., Eid, N. A. S., & Menon, M. (2025) · Molecular and Cellular Biology · doi:10.1080/10985549.2025.2454421 · Cited by 4
Deciphering UBE4B phosphorylation dynamics: a key mechanism in p53 accumulation and cancer cell response to DNA damage
Abuetabh, Y., Wu, H. H., Yousef, H. A., Persad, S., Schlosser, M.-P., Eisenstat, D. D., Sergi, C. M., & Leng, R. P. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02441-9 · Cited by 4
“VE-821 is a potent ATR inhibitor that has been shown to effectively suppress a variety of solid malignancies [45 – 49].”
Synthetic lethality in personalized cancer therapy
Pang, Y. K., Cheng, M., Chen, M., Zhao, K., Yin, Y., Liu, M., Zhang, J., & Zhong, C. (2022) · Genome Instability & Disease · doi:10.1007/s42764-022-00080-3 · Cited by 4
Non-linear IV pharmacokinetics of the ATR inhibitor berzosertib (M6620) in mice
Deppas, J. J., Kiesel, B. F., Guo, J., Parise, R. A., Clump, D. A., D’Argenio, D. Z., Bakkenist, C. J., & Beumer, J. H. (2024) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-024-04675-3 · Cited by 4
“Preclinical and clinical investigations of ber-zosertib have shown it to exert antitumor activity as both a monotherapy and in combination with DNA-damaging agents, such as cisplatin and IR, especially in p53-deficient cell lines [10–12].”
Targeting ATM for Cancer Therapy: Prospects for Drugging ATM
Hickson, I., Pike, K. G., & Durant, S. T. (2018) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-3-319-75836-7_8 · Cited by 4
The dichotomous effects of caffeine on homologous recombination in mammalian cells
Magwood, A. C., Mundia, M. M., Pladwig, S., Mosser, D. D., & Baker, M. D. (2020) · DNA repair · doi:10.1016/j.dnarep.2020.102805 · Cited by 4

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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