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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Background
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Background
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BackgroundInfluential
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Background
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Background
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Background
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Background
ATR inhibition preferentially targets homologous recombination-deficient tumor cells
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Background
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Method
Human cancer cells utilize mitotic DNA synthesis to resist replication stress at telomeres regardless of their telomere maintenance mechanism
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Method
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Background
Most hydrogen peroxide-induced histone H2AX phosphorylation is mediated by ATR and is not dependent on DNA double-strand breaks
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Background
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Background
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Background
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Background
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Abdel-Fatah, T. M. A., Middleton, F. K., Arora, A., Agarwal, D., Chen, T., Moseley, P. M., Perry, C., Doherty, R. E., Chan, S. Y. T., Green, A. R., et al. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.10.013 · Cited by 86
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Background
Targeting ATR in cancer medicine
Sundar, R., Brown, J. S., Garces, A. I., & Yap, T. A. (2017) · Current Problems in Cancer · doi:10.1016/j.currproblcancer.2017.05.002 · Cited by 83
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Method
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Background
Inherited DNA lesions determine G1 duration in the next cell cycle
Lezaja, A., & Altmeyer, M. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1383578 · Cited by 84
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Background
ATR maintains select progenitors during nervous system development
Lee, Y., Shull, E. R. P., Frappart, P., Katyal, S., Enriquez-Rios, V. D., Zhao, J., Russell, H. R., Brown, E. J., & McKinnon, P. J. (2012) · The EMBO Journal · doi:10.1038/emboj.2011.493 · Cited by 78
“However, recently p53 loss was shown to exacerbate the effects of Atr deﬁciency because this abrogated two separate replication checkpoints (Murga et al , 2009; Ruzankina et al , 2009; Reaper et al , 2011).”
Distinct genetic control of homologous recombination repair of Cas9-induced double-strand breaks, nicks and paired nicks
Vriend, L. E. M., Prakash, R., Chen, C.-C., Vanoli, F., Cavallo, F., Zhang, Y., Jasin, M., & Krawczyk, P. M. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw179 · Cited by 77
“To test their involvement in nickHR, we applied chemical inhibitors KU55933 (ATM) and VE-821 (ATR) to transfected U2OSDR-GFP cells.”
Method
Translational and clinical implications of the genetic landscape of prostate cancer
Spratt, D. E., Zumsteg, Z. S., Feng, F. Y.-C., & Tomlins, S. A. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.76 · Cited by 78
A Surveillance Mechanism Ensures Repair of DNA Lesions during Zygotic Reprogramming
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FANCI Regulates Recruitment of the FA Core Complex at Sites of DNA Damage Independently of FANCD2
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“ATR specific inhibitor (VE-821) [34], but not ATM inhibitor, impaired the formation of both FA core complex and FANCD2 foci (Fig 3B and S3C, S6C and S6D Fig), indicating that ATR kinase activity is required for FA core complex foci formation.”
Background
Targeting the DNA Damage Response to Overcome Cancer Drug Resistance in Glioblastoma
Ferri, A., Stagni, V., & Barilà, D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21144910 · Cited by 83
The Chromatin Response to Double-Strand DNA Breaks and Their Repair
Aleksandrov, R., Hristova, R. H., Stoynov, S., & Gospodinov, A. G. (2020) · Cells · doi:10.3390/cells9081853 · Cited by 79
Inhibition of BUB1 Kinase by BAY 1816032 Sensitizes Tumor Cells toward Taxanes, ATR, and PARP Inhibitors In Vitro and In Vivo
Siemeister, G., Mengel, A., Fernández‐Montalván, A. E., Bone, W., Schröder, J. M., Zitzmann-Kolbe, S., Briem, H., Prechtl, S., Holton, S. J., Mönning, U., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0628 · Cited by 76
“As ATM loss-of-function mutations are synthetically lethal with interference with ATR signaling (26), we hypothesized that inhibition of BUB1 kinase could be synthetically lethal with ATR kinase inhibition aswell.”
Background
Nek1 kinase associates with ATR–ATRIP and primes ATR for efficient DNA damage signaling
Liu, S., Ho, C. K., Ouyang, J., & Zou, L. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217781110 · Cited by 76
“The effectiveness of VE-821 was confirmed by the dephosphorylation of Chk1 Ser-345.”
BackgroundMethodInfluential
Curcumin suppresses multiple DNA damage response pathways and has potency as a sensitizer to PARP inhibitor
Ogiwara, H., Ui, A., Shiotani, B., Zou, L., Yasui, A., & Kohno, T. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt240 · Cited by 76
Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance
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Inhibiting the DNA damage response as a therapeutic manoeuvre in cancer
Curtin, N. J. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12244 · Cited by 78
“Secondly, VE-821, VE-822, NU6027 and AZ-20 have been identified as being ATR inhibitors (Charrier et al., 2011; Peasland et al., 2011; Reaper et al., 2011; Fokas et al., 2012; Jacq et al., 2012) (Figure 8).”
Background
ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications
Armstrong, S. A., Schultz, C. W., Azimi-Sadjadi, A., Brody, J. R., & Pishvaian, M. J. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0208 · Cited by 78
“The ATR inhibitor VE-821 sensitizes cancer cells but not normal cells to chemotherapy (87), and these effects were synergistic in ATM-deficient cells (87).”
Background
Targeting ATM and ATR for cancer therapeutics: Inhibitors in clinic
Priya, B., Ravi, S., & Kirubakaran, S. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103662 · Cited by 77
Development of Synthetic Lethality Anticancer Therapeutics
Fang, B. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm500415t · Cited by 73
Structure and bioactivity of colibactin
Wernke, K. M., Xue, M., Tirla, A., Kim, C. S., Crawford, J. M., & Herzon, S. B. (2020) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2020.127280 · Cited by 74
Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL -rearranged AML
Morgado-Palacin, I., Day, A., Murga, M., Lafarga, V., Antón, M. E., Tubbs, A., Chen, H.-T., Ergen, A. V., Anderson, R., Bhandoola, A., et al. (2016) · Science Signaling · doi:10.1126/scisignal.aad8243 · Cited by 73
ATM: Functions of ATM Kinase and Its Relevance to Hereditary Tumors
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Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition
Middleton, F. K., Patterson, M. J., Elstob, C. J., Fordham, S. E., Herriott, A., Wade, M., McCormick, A., Edmondson, R. J., May, F. E. B., Allan, J. M., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.6136 · Cited by 70
Hereditary breast cancer: ever more pieces to the polygenic puzzle
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“The concept of “synthetic lethality” as exemplified by the introduction of PARP1 inhibitors into treatment of patients with BRCA1 or BRCA2 mutations may also prove useful in the development of other compounds to target additional genetic predispositions [156-158].”
Background
A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer
Konstantinopoulos, P. A., da Costa, A. A. B. A., Gulhan, D., Lee, E. K., Cheng, S., Hendrickson, A. E. W., Kochupurakkal, B. S., Kolin, D. L., Kohn, E. C., Liu, J. F., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25904-w · Cited by 69
Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets
Khamidullina, A. I., Abramenko, Y. E., Bruter, A. V., & Tatarskiy, V. V. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25021263 · Cited by 73
“Several key studies demonstrated that genetic inactivation of ATR leads to synthetic lethality in ATM or TP53 mutated tumors, paving the way to use of small-molecule ATR inhibitors (ATRi) [11,12].”
Background
A patient-derived-xenograft platform to study BRCA-deficient ovarian cancers
George, E. M., Kim, H., Krepler, C., Wenz, B. M., Makvandi, M., Tanyi, J. L., Brown, E. J., Zhang, R., Brafford, P. A., Jean, S., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.89760 · Cited by 71
Differential Activity of ATR and WEE1 Inhibitors in a Highly Sensitive Subpopulation of DLBCL Linked to Replication Stress
Young, L. A., O’Connor, L. O., de Renty, C., Veldman-Jones, M. H., Dorval, T., Wilson, Z., Jones, D. R., Lawson, D., Odedra, R., Maya‐Mendoza, A., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-2480 · Cited by 71
“Cell-cycle dysregulation contributes to RS,with reports suggesting selective toxicity of ATR and CHK1 inhibitors in TP53-defective cells (30, 31).”
Background
Early TP53 alterations engage environmental exposures to promote gastric premalignancy in an integrative mouse model
Sethi, N. S., Kikuchi, O., Duronio, G. N., Stachler, M. D., McFarland, J. M., Ferrer-Luna, R., Zhang, Y., Bao, C., Bronson, R. T., Patil, D. T., et al. (2020) · Nature Genetics · doi:10.1038/s41588-019-0574-9 · Cited by 69
The role of ATM mutations and 11q deletions in disease progression in chronic lymphocytic leukemia
Stanković, T., & Skowrońska, A. (2013) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2013.829919 · Cited by 77
ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways
Le, T. M., Poddar, S., Capri, J. R., Abt, E. R., Kim, W., Liu, W., Uong, N. T., Cheng, C., Braas, D., Nikanjam, M., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00221-3 · Cited by 67
Breaking the DNA damage response to improve cervical cancer treatment
Wieringa, H. W., van der Zee, A. G. J., de Vries, E. G. E., & van Vugt, M. A. T. M. (2015) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2015.11.008 · Cited by 66
“Whereas in vitro work with its analog VE-821 enhanced radiosensitivity in cervical cancer cells [109], in vivo studies with VE-822 showed increased sensitivity to ionizing radiation and gemcitabine in mice xenografts with TP53-mutant pancreatic cancer cells [110].”
Background
CH-01 is a Hypoxia-Activated Prodrug That Sensitizes Cells to Hypoxia/Reoxygenation Through Inhibition of Chk1 and Aurora A
Cázares-Körner, C., Pires, I. M., Swallow, I. D., Grayer, S. C., O’Connor, L. J., Olcina, M. M., Christlieb, M., Conway, S. J., & Hammond, E. M. (2013) · ACS Chemical Biology · doi:10.1021/cb4001537 · Cited by 68
Cancer Cells with Alternative Lengthening of Telomeres Do Not Display a General Hypersensitivity to ATR Inhibition
Deeg, K. I., Chung, I., Bauer, C., & Rippe, K. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00186 · Cited by 65
PARP Inhibitors for Ovarian Cancer: Current Indications, Future Combinations, and Novel Assets in Development to Target DNA Damage Repair
Konstantinopoulos, P. A., Lheureux, S., & Moore, K. N. (2020) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_288015 · Cited by 65
RNF126‐Mediated MRE11 Ubiquitination Activates the DNA Damage Response and Confers Resistance of Triple‐Negative Breast Cancer to Radiotherapy
Liu, W., Zheng, M., Zhang, R., Jiang, Q., Du, G., Wu, Y., Yang, C., Li, F., Li, W., Wang, L., et al. (2022) · Advanced Science · doi:10.1002/advs.202203884 · Cited by 64
Emerging strategies for cancer therapy by ATR inhibitors
Yano, K., & Shiotani, B. (2023) · Cancer Science · doi:10.1111/cas.15845 · Cited by 67
Hyperactivation of ATM upon DNA-PKcs inhibition modulates p53 dynamics and cell fate in response to DNA damage
Finzel, A., Grybowski, A., Strasen, J., Cristiano, E., & Loewer, A. (2016) · Molecular Biology of the Cell · doi:10.1091/mbc.e16-01-0032 · Cited by 65
“In order to systematically study the role of all three PI3K-like kinases in shaping the p53 response, we used well-characterized small molecule inhibitors (KU-55933 - ATMi, VE-821 ATRi and NU 7026 - DNA-PKi) and confirmed their specificity using western blot analysis (Supplementary Figure S1F) (Hickson, 2004; Reaper e…”
Method
Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitor
Iwai, K., Nambu, T., Dairiki, R., Ohori, M., Yu, J., Burke, K. E., Gotou, M., Yamamoto, Y., Ebara, S., Shibata, S., et al. (2019) · Science Advances · doi:10.1126/sciadv.aav3660 · Cited by 63
ATM and ATR Activities Maintain Replication Fork Integrity during SV40 Chromatin Replication
Sowd, G. A., Li, N. Y., & Fanning, E. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003283 · Cited by 63
“The central roles of ATM and ATR in genome maintenance suggest the potential to manipulate their activity for cancer chemotherapy, fueling the development of potent small molecules that specifically inhibit ATM and ATR activities in cellulo [12,13].”
BackgroundMethodInfluential
A haploid genetic screen identifies the G 1 /S regulatory machinery as a determinant of Wee1 inhibitor sensitivity
Heijink, A. M., Blomen, V. A., Bisteau, X., Degener, F., Matsushita, F. Y., Kaldis, P., Foijer, F., & van Vugt, M. A. T. M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1505283112 · Cited by 62
“Preclinical research, however, has shown that the efficacy of therapeutic checkpoint inhibition is context-sensitive and depends on the genetic make-up of an individual cancer (2, 3).”
Background
Alternative lengthening of telomeres (ALT) influences survival in soft tissue sarcomas: a systematic review with meta-analysis
Lawlor, R. T., Veronese, N., Pea, A., Nottegar, A., Smith, L., Pilati, C., Demurtas, J., Fassan, M., Cheng, L., & Luchini, C. (2019) · BMC Cancer · doi:10.1186/s12885-019-5424-8 · Cited by 62
Single-nucleosome imaging reveals steady-state motion of interphase chromatin in living human cells
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Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors
Henssen, A. G., Reed, C., Jiang, E., García, H. D., von Stebut, J., MacArthur, I. C., Hundsdoerfer, P., Kim, J. H., de Stanchina, E., Kuwahara, Y., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aam9078 · Cited by 60
Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer
Galsky, M. D., Guan, X., Rishipathak, D., Rapaport, A. S., Shehata, H. M., Banchereau, R., Yuen, K. C. Y., Varfolomeev, E. E., Hu, R., Han, C.-J., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101393 · Cited by 63
“ATR inhibition at doses that did not impact cell viability (Figure S7), but were consistent with doses previously shown to selectively inhibit ATR in cellular systems, 32 abrogated cisplatin-induced upregulation of surface PD-L1 expression or CXCL10 secretion (Figures 5D and S8).”
Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor
Knegtel, R. M. A., Charrier, J., Durrant, S. J., Davis, C., O’Donnell, M., Storck, P., MacCormick, S., Kay, D. P., Pinder, J. L., Virani, A., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00426 · Cited by 61
Restoring p53 Function in Head and Neck Squamous Cell Carcinoma to Improve Treatments
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“In cells with wild-type p53 (WT p53), double- and singlestranded breaks in the DNA activate kinases such as ataxiatelangiectasia mutated (ATM) and ATM and Rad3 related (ATR), respectively (11), which in turn directly phosphorylate p53 at Ser-15 and will activate checkpoint kinase 2 (CHK2) and checkpoint kinase 1 (CHK1…”
Background
DNA damage response (DDR) pathway engagement in cisplatin radiosensitization of non-small cell lung cancer
Sears, C. R., Cooney, S. A., Chin-Sinex, H., Mendonca, M. S., & Turchi, J. J. (2016) · DNA repair · doi:10.1016/j.dnarep.2016.02.004 · Cited by 60
Checkpoint Kinase 1 Inhibition Enhances Cisplatin Cytotoxicity and Overcomes Cisplatin Resistance in SCLC by Promoting Mitotic Cell Death
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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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