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
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
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Somatic mutations affect key pathways in lung adenocarcinoma
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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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KHDC3L mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells
Zhang, W., Chen, Z., Zhang, D., Zhao, B., Liu, L., Xie, Z., Yao, Y., & Zheng, P. (2019) · PLoS Biology · doi:10.1371/journal.pbio.3000468 · Cited by 59
BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in Myc-induced lymphoma cells
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ATR Is a Therapeutic Target in Synovial Sarcoma
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“As defects in DDR pathways, such as ATM and ATR activation, have been associated with increased ATRi sensitivity (33, 37), we assessed whether defects in ATM/ATR activation following DNA damage in SS tumor cell lines could explain the ATRi sensitivity.”
ATR controls cellular adaptation to hypoxia through positive regulation of hypoxia-inducible factor 1 (HIF-1) expression
Fallone, F., Britton, S., Nieto, L., Salles, B., & Muller, C. (2012) · Oncogene · doi:10.1038/onc.2012.462 · Cited by 56
The APC/C cofactor Cdh1 prevents replicative stress and p53-dependent cell death in neural progenitors
Eguren, M., Porlan, E., Manchado, E., García-Higuera, I., Cañamero, M., Fariñas, I., & Malumbres, M. (2013) · Nature Communications · doi:10.1038/ncomms3880 · Cited by 57
Downregulation of Wip1 phosphatase modulates the cellular threshold of DNA damage signaling in mitosis
Macůrek, L., Benada, J., Müllers, E., Halim, V. A., Krejčíková, K., Burdová, K., Pecháčková, S., Hodný, Z., Lindqvist, A., Medema, R. H., et al. (2013) · Cell Cycle · doi:10.4161/cc.23057 · Cited by 56
DNA-PK triggers histone ubiquitination and signaling in response to DNA double-strand breaks produced during the repair of transcription-blocking topoisomerase I lesions
Cristini, A., Park, J.-H., Capranico, G., Legube, G., Favre, G., & Sordet, O. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1196 · Cited by 60
“BrdU, CPT, FLV, MG132, Pyr-41 (35) and 4- hydroxitamoxifen (4OHT) were obtained from SigmaAldrich; lactacystin, G5 (36), KU55933 (37) and VE-821 (38) from Millipore; bortezomib, veliparib and olaparib from Selleckchem; and NU7441 (39) from Tocris.”
Targeting DNA damage in SCLC
Foy, V., Schenk, M. W., Baker, K., Gomes, F., Lallo, A., Frese, K. K., Forster, M. D., Dive, C., & Blackhall, F. H. (2017) · Lung Cancer · doi:10.1016/j.lungcan.2017.10.006 · Cited by 54
“may result in synthetic lethality [93].”
Loss of Cyclin C or CDK8 provides ATR inhibitor resistance by suppressing transcription-associated replication stress
Lloyd, R. L., Urban, V., Muñoz‐Martínez, F., Ayestaran, I., Thomas, J. C., de Renty, C., O’Connor, M. J., Forment, J. V., Galanty, Y., & Jackson, S. P. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab628 · Cited by 56
“However, rather than causing resistance, p53 loss caused sensitivity to AZD6738, consistent with previous reports (15,16,52).”
Result
First-in-Human Study of the Ataxia Telangiectasia and Rad3-Related (ATR) Inhibitor Tuvusertib (M1774) as Monotherapy in Patients with Solid Tumors
Yap, T. A., Tolcher, A. W., Plummer, R., Mukker, J. K., Enderlin, M., Hicking, C., Grombacher, T., Locatelli, G., Szűcs, Z., Gounaris, I., et al. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-2409 · Cited by 57
ATR inhibition sensitizes HPV− and HPV+ head and neck squamous cell carcinoma to cisplatin
Leonard, B. C., Lee, E. D., Bhola, N. E., Li, H., Sogaard, K. K., Bakkenist, C. J., Grandis, J. R., & Johnson, D. E. (2019) · Oral Oncology · doi:10.1016/j.oraloncology.2019.05.028 · Cited by 53
“A, HNSCC cell lines were transfected with nontargeting siRNA (siNT) or siRNAs directed against ATR, ATM, or p53 mRNAs, as described in Materials and Methods.”
BackgroundInfluential
Quantitative Chemical Proteomic Profiling of Ubiquitin Specific Proteases in Intact Cancer Cells
Ward, J., McLellan, L., Stockley, M. L., Gibson, K. R., Whitlock, G. A., Knights, C., Harrigan, J. A., Jacq, X., & Tate, E. W. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.6b00766 · Cited by 54
ATR Restrains DNA Synthesis and Mitotic Catastrophe in Response to CDC7 Inhibition
Rainey, M. D., Bennett, D., O’Dea, R., Zanchetta, M. E., Voisin, M., Seoighe, C., & Santocanale, C. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108096 · Cited by 54
ATR inhibition enables complete tumour regression in ALK-driven NB mouse models
Szydzik, J., Lind, D. E., Arefin, B., Kurhe, Y., Umapathy, G., Siaw, J. T., Claeys, A., Gabre, J. L., den Eynden, J. V., Hallberg, B., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27057-2 · Cited by 51
The identification of the ATR inhibitor VE-822 as a therapeutic strategy for enhancing cisplatin chemosensitivity in esophageal squamous cell carcinoma
Shi, Q. W., Shen, L., Dong, B., Fu, H., Kang, X., Yang, Y., Dai, L. X., Yan, W., Xiong, H., Liang, Z., et al. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.06.010 · Cited by 52
ATR-mediated proteome remodeling is a major determinant of homologous recombination capacity in cancer cells
Kim, D.-S., Liu, Y., Oberly, S., Freire, R., & Smolka, M. B. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky625 · Cited by 53
SMARCA4 deficiency-associated heterochromatin induces intrinsic DNA replication stress and susceptibility to ATR inhibition in lung adenocarcinoma
Kurashima, K., Kashiwagi, H., Shimomura, I., Suzuki, A., Takeshita, F., Mazevet, M., Harata, M., Yamashita, T., Yamamoto, Y., Kohno, T., et al. (2020) · NAR Cancer · doi:10.1093/narcan/zcaa005 · Cited by 53
“Preclinical studies found that ATRis induced both chemo-and radiosensitization (63–69).”
TP53 mutations increase radioresistance in rhabdomyosarcoma and Ewing sarcoma
Casey, D. L., Pitter, K. L., Wexler, L. H., Slotkin, E. K., Gupta, G. P., & Wolden, S. L. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01438-2 · Cited by 51
“Accordingly, inhibition of CHK1 has been shown to selectively overcome the radioresistance of TP53 mutated cells in response to radiation and other DNA damaging agents; and ATR inhibitors have also been shown to induce synthetic lethality in TP53 disruptive cells.(27,28) Other strategies to mitigate radioresistance ma…”
Background
Exploiting the p53 Pathway for TherapyPreprint
Cheok, C. F., & Lane, D. P. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026310 · Cited by 53
“…in genotoxicity in the p53-deficient cells toward radiation and different genotoxic agents, including cisplatin, campthothecin, and doxorubicin, as a consequence of the combined loss of G1 and G2/M checkpoints (Russell et al. 1995; Wang et al. 1996; Nghiem et al. 2001, 2002; Reaper et al. 2011).”
BackgroundInfluential
Combined poly-ADP ribose polymerase and ataxia-telangiectasia mutated/Rad3-related inhibition targets ataxia-telangiectasia mutated-deficient lung cancer cells
Jette, N., Radhamani, S., Arthur, G., Ye, R., Goutam, S., Bolyos, A., Petersen, L. F., Bose, P., Bebb, D. G., & Lees‐Miller, S. P. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0565-8 · Cited by 50
Targeting Ongoing DNA Damage in Multiple Myeloma: Effects of DNA Damage Response Inhibitors on Plasma Cell Survival
Herrero, A. B., & Gutierrez, N. C. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00098 · Cited by 50
“(B) Cell survival after 72 h in the absence (untreated = UT) or the presence of 10 µM KU-55933, 5 µM VE-821, or both.”
ResultInfluential
Diverse roles of RAD18 and Y-family DNA polymerases in tumorigenesis
Yang, Y., Gao, Y., Zlatanou, A., Tateishi, S., Yurchenko, V., Rogozin, I. B., & Vaziri, C. (2018) · Cell Cycle · doi:10.1080/15384101.2018.1456296 · Cited by 52
“ATR inhibitors sensitize tumor cells to overexpressed Cyclin E [102] and therapeutic genotoxins notably platinating agents [103,104].”
Rationally Designed PI3Kα Mutants to Mimic ATR and Their Use to Understand Binding Specificity of ATR Inhibitors
Lu, Y., Knapp, M. S., Crawford, K. R., Warne, R. L., Elling, R. A., Yan, K., Doyle, M., Pardee, G., Zhang, L., Ma, S., et al. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.04.006 · Cited by 49
Natural products targeting the ATR-CHK1 signaling pathway in cancer therapy
Ahmed, S., Alam, W., Aschner, M., Alsharif, K. F., Albrakati, A., Saso, L., & Khan, H. Z. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113797 · Cited by 51
“The very first ATR antagonist to enter human anti-cancer therapeutic studies was VX-970 (VE-822), a powerful selective intravenous ATR blocker [102].”
Background
Preclinical testing of an ATR inhibitor demonstrates improved response to standard therapies for esophageal cancer
Leszczyńska, K. B., Dobrynin, G., Leslie, R. E., Ient, J., Boumelha, A. J., Senra, J. M., Hawkins, M., Maughan, T., Mukherjee, S., & Hammond, E. M. (2016) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2016.10.023 · Cited by 48
“In addition, ATR inhibition has been shown to be particularly cytotoxic to tumor cells with a deficiency in the ATM or p53 pathway [3,7].”
Background
CDK8/19 inhibition induces premature G1/S transition and ATR-dependent cell death in prostate cancer cells
Nakamura, A., Nakata, D., Kakoi, Y., Kunitomo, M., Murai, S., Ebara, S., Hata, A., & Hara, T. (2018) · Oncotarget · doi:10.18632/oncotarget.24414 · Cited by 50
VE-821, an ATR inhibitor, causes radiosensitization in human tumor cells irradiated with high LET radiation
Fujisawa, H., Nakajima, N. I., Sunada, S., Lee, Y., Hirakawa, H., Yajima, H., Fujimori, A., Uesaka, M., & Okayasu, R. (2015) · Radiation Oncology · doi:10.1186/s13014-015-0464-y · Cited by 48
“This chemical is also known to inhibit chk1 phosphorylation [10, 11].”
Background
ATM/Wip1 activities at chromatin control Plk1 re‐activation to determine G2 checkpoint duration
Jaiswal, H., Benada, J., Müllers, E., Akopyan, K., Burdová, K., Koolmeister, T., Helleday, T., Medema, R. H., Macůrek, L., & Lindqvist, A. (2017) · The EMBO Journal · doi:10.15252/embj.201696082 · Cited by 45
“Key targets of Chk1/Chk2/MK2 are Cdc25 phosphatases and their degradation or functional inactivation results in a rapid decrease in Cdk1 activity and suppression of cell cycle progression (Peng et al , 1997; Mailand et al , 2000; Reinhardt et al , 2007).”
PLK1 Inhibition Targets Myc-Activated Malignant Glioma Cells Irrespective of Mismatch Repair Deficiency–Mediated Acquired Resistance to Temozolomide
Higuchi, F., Fink, A. L., Kiyokawa, J., Miller, J. J., Koerner, M. V. A., Cahill, D. P., & Wakimoto, H. (2018) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-18-0177 · Cited by 46
“Volasertib (23), Irinotecan, KU-55933 (24), VE-821 (25), Alisertib (26), Barasertib (27), MK8776 (28), NU7441 (29), Palbociclib, Carboplatin, and Imatinib were purchased from SelleckChem.”
REV 7 confers radioresistance of esophagus squamous cell carcinoma by recruiting PRDX 2
Gu, C., Luo, J., Lu, X., Tang, Y., Ma, Y., Yun, Y., Cao, J., Cao, J., Huang, Z., Zhou, X., et al. (2019) · Cancer Science · doi:10.1111/cas.13946 · Cited by 47
ATM protein is deficient in over 40% of lung adenocarcinomas
Villaruz, L. C., Jones, H., Đačić, S., Abberbock, S. R., Kurland, B. F., Stabile, L. P., Siegfried, J. M., Conrads, T. P., Smith, N. R., O’Connor, M. J., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.9757 · Cited by 46
“Lung cancer cell lines are sensitized to cisplatin by ATR kinase inhibitors in vitro and in cell line and patient derived xenografts (PDX) in vivo [16, 17, 36, 37].”
Background
Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma
Southgate, H. E. D., Chen, L., Curtin, N. J., & Tweddle, D. A. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00371 · Cited by 48
“Both amplification of MYCN and impaired ATM function, which result in replication stress and defects in G1 cell cycle control, are known determinants of sensitivity to ATR inhibitors (105, 136).”
Background
Ataxia Telangiectasia Mutated (ATM) Is Dispensable for Endonuclease I-SceI-induced Homologous Recombination in Mouse Embryonic Stem Cells
Rass, E., Chandramouly, G., Zha, S., Alt, F. W., & Xie, A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.445825 · Cited by 43
“Thus, we used the newly developed, potent ATR inhibitor VE821 to assess the effect of ATR inhibition on IR-induced H2AX phosphorylation (42).”
Method
Targeting DNA double-strand break signalling and repair: recent advances in cancer therapy
Hühn, D., Bolck, H. A., & Sartori, A. A. (2013) · Swiss Medical Weekly · doi:10.4414/smw.2013.13837 · Cited by 53
Hypoxic Stress Facilitates Acute Activation and Chronic Downregulation of Fanconi Anemia Proteins
Scanlon, S. E., & Glazer, P. M. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-13-0628 · Cited by 45
“2B, lanes 13 and 23), as has been observed in another study (37).”
Result
MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated
Smida, M., Fece de la Cruz, F., Kerzendorfer, C., Uras, I. Z., Mair, B., Mazouzi, A., Suchankova, T., Konopka, T., Katz, A. M., Paz, K., et al. (2016) · Nature Communications · doi:10.1038/ncomms13701 · Cited by 44
Exploiting Synthetic Lethal Interactions Between DNA Damage Signaling, Checkpoint Control, and p53 for Targeted Cancer Therapy
Morandell, S., & Yaffe, M. B. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-387665-2.00011-0 · Cited by 45
Synergism between ATM and PARP1 Inhibition Involves DNA Damage and Abrogating the G2 DNA Damage Checkpoint
Mak, J. P. Y., Ma, H. T., & Poon, R. Y. C. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0474 · Cited by 44
Targeting CDC7 potentiates ATR-CHK1 signaling inhibition through induction of DNA replication stress in liver cancer
Guo, Y., Wang, J., Benedict, B., Yang, C. G., van Gemert, F. P. A., Ma, X., Gao, D., Wang, H., Zhang, S., Lieftink, C., et al. (2021) · Genome Medicine · doi:10.1186/s13073-021-00981-0 · Cited by 45
Targeting the ATM pathway in cancer: Opportunities, challenges and personalized therapeutic strategies
Lee, J. (2024) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2024.102808 · Cited by 50
Ataxia Telangiectasia Mutated Protein Loss and Benefit From Oxaliplatin-based Chemotherapy in Colorectal Cancer
Sundar, R., Miranda, S., Rodrigues, D. N., Chénard-Poirier, M., Dolling, D. I., Clarke, M., Figueiredo, I., Bertan, C. M., Yuan, W., Ferreira, A., et al. (2018) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2018.05.011 · Cited by 41
Genomic and Clinicopathologic Characterization of ATM -deficient Prostate Cancer
Kaur, H. B., Salles, D. C., Murali, S., Hicks, J. L., Nguyen, M., Pritchard, C. C., Marzo, A. M. D., Lanchbury, J. S. S., Trock, B. J., Isaacs, W. B., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-0764 · Cited by 46
“However, several potent and relatively specific ATR inhibitors have been characterized and have shown synthetic lethal activity in ATM-deficient tumors in vitro and in early clinical trials (18, 19).”
Background
PARP Inhibition Increases the Reliance on ATR/CHK1 Checkpoint Signaling Leading to Synthetic Lethality—An Alternative Treatment Strategy for Epithelial Ovarian Cancer Cells Independent from HR Effectiveness
Gralewska, P., Gajek, A., Marczak, A., Mikuła, M., Ostrowski, J., Śliwińska, A., & Rogalska, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249715 · Cited by 45
“Combination treatment with two compounds, PARPi and CHK1i, had a significantly greater cytotoxic effect, decreasing colony formation ability to a greater extent than either drug alone in BRCA2MUT cells compared with BRCAWT.”
BackgroundInfluential
Synthetic Lethality in Ovarian Cancer
Chandrasekaran, A., & Elias, K. M. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-21-0500 · Cited by 41
“16 (69), components of the PI3-kinase signaling pathway (70), the DNA-damage checkpoint kinase 363 CHK1 (71,72), and a key determinant of replication fork stability, ATR (ataxia telangiectasia and 364 RAD3-related) (73,74).”
Background
A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours
Burris, H. A., Berlin, J. D., Arkenau, H., Cote, G. M., Lolkema, M. P., Ferrer-Playan, J., Kalapur, A., Bolleddula, J., Locatelli, G., Goddemeier, T., et al. (2024) · British Journal of Cancer · doi:10.1038/s41416-023-02436-2 · Cited by 44
DNA Replication Stress and Cancer: Cause or Cure?
Taylor, E. M., & Lindsay, H. D. (2015) · Future Oncology · doi:10.2217/fon.15.292 · Cited by 44
Senescence Induction by Combined Ionizing Radiation and DNA Damage Response Inhibitors in Head and Neck Squamous Cell Carcinoma Cells
Dobler, C., Jost, T., Hecht, M., Fietkau, R., & Distel, L. V. (2020) · Cells · doi:10.3390/cells9092012 · Cited by 41
“In line with this finding, inhibition of ATR/ATM or Chk1/Chk2 was found to delay the onset of replicative senescence [24].”
BackgroundInfluential
Modulation of DNA repair by pharmacological inhibitors of the PIKK protein kinase family
Finlay, M. R. V., & Griffin, R. J. (2012) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2012.06.053 · Cited by 40
A Synthetic Interaction Screen Identifies Factors Selectively Required for Proliferation and TERT Transcription in p53-Deficient Human Cancer Cells
Xie, L., Gazin, C., Park, S. M., Zhu, L. J., Debily, M.-A., Kittler, E. L. W., Zapp, M. L., Lapointe, D. S., Gobeil, S., Virbasius, C.-M. A., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1003151 · Cited by 41
“For example, p532 cells have been found to be particularly sensitive to pharmacological inhibition of ATR (see, for example, [42–44]).”
Background
A synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers
Hocke, S., Guo, Y., Job, A., Orth, M., Ziesch, A., Lauber, K., Toni, E. N. D., Gress, T. M., Herbst, A., Göke, B., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.6857 · Cited by 40
Targeting PARP1 to Enhance Anticancer Checkpoint Immunotherapy Response: Rationale and Clinical Implications
Wanderley, C. W. S., Corrêa, T. S., Scaranti, M., Cunha, F. Q., & Barroso‐Sousa, R. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.816642 · Cited by 40
“In a large proportion of cancer cells, where ATM-p53 signaling is defective, initiation of DNA replication continues and DNA damage accumulates, leading to cell death (72).”
Background
Phase 1b study of berzosertib and cisplatin in patients with advanced triple-negative breast cancer
Telli, M. L., Tolaney, S. M., Shapiro, G. I., Middleton, M. R., Lord, S., Arkenau, H., Tutt, A. N. J., Abramson, V. G., Dean, E. J., Haddad, T. C., et al. (2022) · npj Breast Cancer · doi:10.1038/s41523-022-00406-0 · Cited by 40
Synthetic Lethal Vulnerabilities of Cancer
de la Cruz, F. F., Gapp, B. V., & Nijman, S. M. B. (2014) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010814-124511 · Cited by 43
Mouse embryonic stem cells have increased capacity for replication fork restart driven by the specific Filia-Floped protein complex
Zhao, B., Zhang, W., Cun, Y., Li, J., Liu, Y., Gao, J. X., Zhu, H., Zhou, H., Zhang, R., & Zheng, P. (2017) · Cell Research · doi:10.1038/cr.2017.139 · Cited by 40
Inhibition of ATR-Dependent Signaling by Protoapigenone and Its Derivative Sensitizes Cancer Cells to Interstrand Cross-link–Generating Agents In Vitro and In Vivo
Wang, H., Lee, A. Y., Chou, W., Wu, C., Tseng, C., Liu, K. Y.-T., Lin, W.-L., Chang, F., Chuang, D., Hunyadi, A., et al. (2012) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0921 · Cited by 39
ATR inhibition rewires cellular signaling networks induced by replication stress
Wagner, S., Oehler, H., Voigt, A., Dalic, D., Freiwald, A., Serve, H. L., & Beli, P. (2015) · PROTEOMICS · doi:10.1002/pmic.201500172 · Cited by 40
“Furthermore, we used a specific ATR inhibitor VE-821 to decipher how ATR inhibition affects cellular signaling after replication stress and to identify phosphorylation sites that are targeted by ATR [42].”
Method
The Impact of p53 Dysfunction in ATR Inhibitor Cytotoxicity and Chemo- and Radiosensitisation
Middleton, F. K., Pollard, J. R., & Curtin, N. J. (2018) · Cancers · doi:10.3390/cancers10080275 · Cited by 39
“Similarly, in isogenic cell lines ATR inhibitors potentiated cisplatin to a greater extent in cells where p53 had been knocked down or degraded [7].”
BackgroundMethod
Nontoxic concentration of DNA ‐ PK inhibitor NU7441 radio‐sensitizes lung tumor cells with little effect on double strand break repair
Sunada, S., Kanai, H., Lee, Y., Yasuda, T., Hirakawa, H., Liu, C., Fujimori, A., Uesaka, M., & Okayasu, R. (2016) · Cancer Science · doi:10.1111/cas.12998 · Cited by 38
ATM inhibition induces synthetic lethality and enhances sensitivity of PTEN-deficient breast cancer cells to cisplatin
Li, K., Yan, H., Guo, W., Tang, M., Zhao, X., Tong, A., Peng, Y., Li, Q., & Yuan, Z. (2018) · Experimental Cell Research · doi:10.1016/j.yexcr.2018.03.006 · Cited by 38
“Synthetic lethal approach is a promising therapy strategy for cancer treatment [39,43,44].”
Background
DNA Repair: Translation to the Clinic
Minten, E. V., & Yu, D. S. (2019) · Clinical Oncology · doi:10.1016/j.clon.2019.02.007 · Cited by 36
“Preclinical studies have found that ATR has a synthetic lethal relationship with several DDR players, including XRCC1 and ATM, and is currently under clinical investigation for its potential as a target in cancer therapies [38,39].”
Background
Modeling of Cisplatin-Induced Signaling Dynamics in Triple-Negative Breast Cancer Cells Reveals Mediators of Sensitivity
Heijink, A. M., Everts, M., Honeywell, M. E., Richards, R., Kok, Y. P., de Vries, E. G. E., Lee, M. J., & van Vugt, M. A. T. M. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.070 · Cited by 37
“, 2012) and that targeting of cell-cycle checkpoints, including ATR, CHK1, and WEE1, can be used to sensitize cancer cells to cisplatin (Gadhikar et al., 2013; Hirai et al., 2009; Perez et al., 2006; Reaper et al., 2011; Sangster-Guity et al., 2011).”
Background
Inhibition of ATR kinase with the selective inhibitor VE-821 results in radiosensitization of cells of promyelocytic leukaemia (HL-60)
Vávrová, J., Zárybnická, L., Lukášová, E., Řezáčová, M., Novotná, E., Šinkorová, Z., Tichý, A., Pejchal, J., & Ďurišová, K. (2013) · Radiation and Environmental Biophysics · doi:10.1007/s00411-013-0486-5 · Cited by 36
Therapeutic Targets and Opportunities in Endometrial Cancer: Update on Endocrine Therapy and Nonimmunotherapy Targeted Options
MacKay, H. J., Freixinos, V. R., & Fleming, G. F. (2020) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_280495 · Cited by 38
ATR Inhibition Potentiates PARP Inhibitor Cytotoxicity in High Risk Neuroblastoma Cell Lines by Multiple Mechanisms
Southgate, H. E. D., Chen, L., Tweddle, D. A., & Curtin, N. J. (2020) · Cancers · doi:10.3390/cancers12051095 · Cited by 35
“Various determinants of ATR inhibitor sensitivity have been proposed, including RS, loss of G1 checkpoint control and loss of the ataxia telangiectasia mutated (ATM) protein [7,8].”
Background
The Mismatch-Binding Factor MutSβ Can Mediate ATR Activation in Response to DNA Double-Strand Breaks
Burdová, K., Mihaljević, B., Sturzenegger, A., Chappidi, N., & Janščák, P. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.06.026 · Cited by 37
Cytoplasmic ATR Activation Promotes Vaccinia Virus Genome Replication
Postigo, A. A., Ramsden, A. E., Howell, M. T., & Way, M. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.04.025 · Cited by 38
“, 2004) (118500, Millipore, 20 mM), VE-821 (ATRi) (Reaper et al., 2011) (A11605, Adooq Bioscience, 20 mM), SB218078 (Chk1i) (559402, Millipore, 5 mM), AZD7762 (Chk1/2i) (SML-0350, Sigma, 2 mM), MG-132 (Sigma, 25 mM), CHX (C7698, Sigma, 50 mM), AraC (C1768, Sigma, 50/5 mM), HAMNO (SML1234, Sigma, 20 mM), KU60019 (HY-12…”
DNA Damage Repair Inhibitors—Combination Therapies
Smith, G., Alholm, Z., Coleman, R. L., & Monk, B. J. (2021) · The Cancer Journal · doi:10.1097/ppo.0000000000000561 · Cited by 35
Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors
Sule, A. D., Doorn, J. V., Sundaram, R. K., Ganesa, S., Vasquez, J. C., & Bindra, R. S. (2021) · NAR Cancer · doi:10.1093/narcan/zcab018 · Cited by 38
Perspectives on cancer therapy—synthetic lethal precision medicine strategies, molecular mechanisms, therapeutic targets and current technical challenges
Peng, S., Long, M., Chen, Q.-S., Yin, Z., Zeng, C., Zhang, W., Wen, Q., Zhang, X., Ke, W., & Wu, Y. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02418-8 · Cited by 38
Building high-resolution synthetic lethal networks: a ‘Google map’ of the cancer cell
Paul, J., Templeton, S. D., Baharani, A., Freywald, A., & Vizeacoumar, F. J. (2014) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2014.09.009 · Cited by 34
Herpes Simplex Virus Type 1 Single Strand DNA Binding Protein and Helicase/Primase Complex Disable Cellular ATR Signaling
Mohni, K. N., Smith, S., Dee, A. R., Schumacher, A. J., & Weller, S. K. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003652 · Cited by 34
“For example, ATM- and p53-deficient tumor cells are very sensitive to ATR inhibition [63], and the combination of oncolytic HSV-1 with conventional chemotherapy has resulted in decreased tumor volume and improved long-term survival in animal models of Glioblastoma multiforme [68,69].”
Background
ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress
Kemp, M. G., & Sancar, A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.719740 · Cited by 35
“Inhibitors of the DNA damage kinases ATR (VE-821 and AZD6738), ataxia telangiectasia-mutated (ATM; KU-55933), DNA-dependent protein kinase (DNA-PK; NU7441), and Checkpoint kinase 1 (CHK1; AZD7762) were purchased from Selleckchem.”
BackgroundResultInfluential
Therapeutic Targeting of the DNA Damage Response Using an ATR Inhibitor in Biliary Tract Cancer
Nam, A., Jin, M. H., Park, J. E., Bang, J., Oh, D., & Bang, Y. (2018) · Cancer Research and Treatment · doi:10.4143/crt.2018.526 · Cited by 33
DNA Damage Response Inhibitor Combinations Exert Synergistic Antitumor Activity in Aggressive B-Cell Lymphomas
Restelli, V., Lupi, M., Chilà, R., Vagni, M., Tarantelli, C., Spriano, F., Gaudio, E., Bertoni, F., Damia, G. L. M., & Carrassa, L. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-18-0919 · Cited by 35
“Since both TP53 and MYC have already been found to be associated with a strong response to ATR inhibitors (19, 28, 29), we looked for a putative association of these molecular features with the degree of sensitivity to AZD6738 in 26 of the 36 B-cell lymphoma cell lines tested (with known functional status for TP53 and…”
BackgroundResult
Crosstalk between P53 and DNA damage response in ageing
Mohammadzadeh, A., Mirza‐Aghazadeh‐Attari, M., Hallaj, S., Saei, A. A., Alivand, M. R., Valizadeh, A., Yousefi, B., & Majidinia, M. (2019) · DNA repair · doi:10.1016/j.dnarep.2019.05.004 · Cited by 34
Targeting DNA damage response components induces enhanced STING-dependent type-I IFN response in ATM deficient cancer cells and drives dendritic cell activation
López‐Peláez, M., Young, L. A., Vázquez–Chantada, M., Nelson, N., Durant, S. T., Wilkinson, R. W., Poon, E., Gaspar, M., Valge-Archer, V., Smith, P. D., et al. (2022) · OncoImmunology · doi:10.1080/2162402x.2022.2117321 · Cited by 37
“Tumor cells with defects in the DNA damage response pathway have been shown to be more susceptible to DNA damage induction(3) and ATR inhibition has been described to induce synthetic lethality in ATM −/− cells.(2,20,24) To confirm these results, we treated FaDu ATM −/− cells with the ATR inhibitor ceralasertib or wit…”
BackgroundMethod
Pold3is required for genomic stability and telomere integrity in embryonic stem cells and meiosis
Zhou, Z., Wang, L., Ge, F., Gong, P., Wang, H., Wang, F., Chen, L., & Liu, L. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky098 · Cited by 34
“Moreover, we used an ATR specific inhibitor VE-821 (43,44), which can induce predominantly replicative stress, to treat shPold3 ESCs compared with shControl.”
Method
Identification of ATR–Chk1 Pathway Inhibitors That Selectively Target p53-Deficient Cells without Directly Suppressing ATR Catalytic Activity
Kawasumi, M., Bradner, J. E., Tolliday, N. J., Thibodeau, R. M., Sloan, H., Brummond, K. M., & Nghiem, P. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-2650 · Cited by 30
“These compounds sensitized cancer cells to cisplatin, while sparing normal cells (15, 16), further supporting the potential utility of ATR inhibition to sensitize cancer cells to death.”
Background
IGF-1R inhibition sensitizes breast cancer cells to ATM-related kinase (ATR) inhibitor and cisplatin
O’Flanagan, C. H., O’Shea, S., Lyons, A., Fogarty, F., McCabe, N., Kennedy, R. D., & O’Connor, R. (2016) · Oncotarget · doi:10.18632/oncotarget.10862 · Cited by 32
“OSI-906 and VE-821 in combination consistently decreased colony growth over the entire range of drug concentrations (Figure 3E).”
MethodInfluential
Brain Distribution of Berzosertib: An Ataxia Telangiectasia and Rad3-Related Protein Inhibitor for the Treatment of Glioblastoma
Talele, S., Zhang, W., Burgenske, D. M., Kim, M., Mohammad, A. S., Dragojevic, S., Gupta, S. K., Bindra, R. S., Sarkaria, J. N., & Elmquist, W. F. (2021) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.121.000845 · Cited by 31
Stella preserves maternal chromosome integrity by inhibiting 5hmC‐induced γH2AX accumulation
Nakatani, T., Yamagata, K., Kimura, T., Oda, M., Nakashima, H., Hori, M., Sekita, Y., Arakawa, T., Nakamura, T., & Nakano, T. (2015) · EMBO Reports · doi:10.15252/embr.201439427 · Cited by 31
“To examine the effect of cH2AX in the development of Stella-null embryos, we inhibited the cH2AX accumulation using various kinase inhibitors [22,23].”
Method
Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer
Yang, S., Kuo, T., Wu, H., Guo, J., Hsu, C., Hsu, C., Tien, Y., Yeh, K., Cheng, A., & Kuo, S. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i32.7275 · Cited by 33
Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis
Shi, Y., Liu, Z., Zhang, Q., Vallee, I., Mo, Z., Kishi, S., & Yang, X. (2020) · PLoS Biology · doi:10.1371/journal.pbio.3000991 · Cited by 31
“(I) ChIP-qPCR to measure the binding of SerRS to VEGFA promoter in HEK293 cells stably transfected with SerRSWT, SerRSAA, or SerRSDD under normoxia or hypoxia, in the presence or absence of VE-821 (means ± SEM, n = 3, biological replicates, ��p 0.01, ��p 0.001, Student t test).”
ResultInfluential
Organoids as a Robust Preclinical Model for Precision Medicine in Colorectal Cancer: A Systematic Review
Flood, M. P., Narasimhan, V., Wilson, K., Lim, W. M., Ramsay, R. G., Michael, M., & Heriot, A. G. (2021) · Annals of Surgical Oncology · doi:10.1245/s10434-021-10829-x · Cited by 32
SV40 Utilizes ATM Kinase Activity to Prevent Non-homologous End Joining of Broken Viral DNA Replication Products
Sowd, G. A., Mody, D., Eggold, J. T., Cortez, D., Friedman, K. L., & Fanning, E. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1004536 · Cited by 29
“ATMi [36], ATRi [35], and Nu7026 [42] were as previously described [30] and used at 10, 5, and 10 mM, respectively.”
Method
Exploiting Replication Stress as a Novel Therapeutic Intervention
Martin, J. C., Hoegel, T. J., Lynch, M. L., Woloszynska‐Read, A., Melendy, T., & Ohm, J. E. (2020) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-20-0651 · Cited by 32
“Inhibitors of ATR, CHK1, and WEE1 have been shown to be efficacious as single agents in the treatment of several forms of cancer including Ewing sarcoma (86), MYC-driven lymphoma (87), p53- and ATM-deficient tumors (88) and certain subsets of lung cancer (89).”
Background
Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers
Dok, R., Glorieux, M., Bamps, M., & Nuyts, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041504 · Cited by 31
“This despite that defective DDR has been reported as a marker for ATR sensitivity [35,39,40] and differences in DDR have been implied as a potential mechanism for ATR-mediated sensitivity to DNA-damaging agents [38].”
Background
A phase 1b study evaluating the safety and preliminary efficacy of berzosertib in combination with gemcitabine in patients with advanced non-small cell lung cancer
Plummer, R., Dean, E. J., Arkenau, H., Redfern, C. H., Spira, A. I., Melear, J. M., Chung, K. Y., Ferrer-Playan, J., Goddemeier, T., Locatelli, G., et al. (2021) · Lung Cancer · doi:10.1016/j.lungcan.2021.11.011 · Cited by 30
CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to event continual reassessment method
Javed, S. R., Lord, S., Badri, S. E., Harman, R., Holmes, J., Kamzi, F., Maughan, T., McIntosh, D., Mukherjee, S., Ooms, A., et al. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02542-1 · Cited by 30
The Mechanism of Action of (−)-Lomaiviticin A
Herzon, S. B. (2017) · Accounts of Chemical Research · doi:10.1021/acs.accounts.7b00347 · Cited by 32
Selective Inhibition of ATM-dependent Double-strand Break Repair and Checkpoint Control Synergistically Enhances the Efficacy of ATR Inhibitors
Turchick, A., Zimmermann, A., Chiu, L.-Y., Dahmen, H., Elenbaas, B., Zenke, F. T., Blaukat, A., & Vassilev, L. T. (2023) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-22-0685 · Cited by 30
“Consistent with previous reports (21), these data suggest that, while the effect of M6620þM3541 combination is cytotoxic in most tested cancer cell lines, it is largely cytostatic in fibroblasts.”
Design, synthesis, and biological characterization of proteolysis targeting chimera (PROTACs) for the ataxia telangiectasia and RAD3-related (ATR) kinase
Alfayomy, A. M., Ashry, R., Kansy, A. G., Sarnow, A., Erdmann, F., Schmidt, M., Krämer, O. H., & Sippl, W. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116167 · Cited by 28
Depletion of ATR selectively sensitizes ATM-deficient human mammary epithelial cells to ionizing radiation and DNA-damaging agents
Cui, Y., Palii, S. S., Innes, C. L., & Paules, R. S. (2014) · Cell Cycle · doi:10.4161/15384101.2014.960729 · Cited by 29
“In another report, ATR inhibition through VE-821, a selective small-molecule inhibitor, showed profound synthetic lethal interaction in cells deficient in ATM-p53 pathway when treated with DNA-damaging agents.(36) Therefore, deficiency in other components in the ATM-CHK2p53 pathway may also sensitize cells to ATR disr…”
Background
Acquired small cell lung cancer resistance to Chk1 inhibitors involves Wee1 up‐regulation
Zhao, X., Kim, I., Kallakury, B., Chahine, J. J., Iwama, E., Pierobon, M., Petricoin, E. F., McCutcheon, J. N., Zhang, Y., Umemura, S., et al. (2020) · Molecular Oncology · doi:10.1002/1878-0261.12882 · Cited by 29
Human DDK rescues stalled forks and counteracts checkpoint inhibition at unfired origins to complete DNA replication
Jones, M. V., Gelot, C., Munk, S., Koren, A., Kawasoe, Y., George, K. A., Santos, R. E., Olsen, J. V., McCarroll, S. A., Frattini, M. G., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.01.004 · Cited by 29
“To determine if ATR acts similarly in DDK-inhibited cells we used VE-821, a validated ATR-selective inhibitor (Reaper et al., 2011).”
Method
Drug and molecular radiotherapy combinations for metastatic castration resistant prostate cancer
Staniszewska, M., Iking, J., Lückerath, K., Hadaschik, B. A., Herrmann, K., Ferdinandus, J., & Fendler, W. P. (2021) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2021.03.009 · Cited by 31
Exploiting DNA Damage Repair in Precision Cancer Therapy: BRCA1 as a Prime Therapeutic Target
Raimundo, L., Calheiros, J., & Saraiva, L. (2021) · Cancers · doi:10.3390/cancers13143438 · Cited by 33
Cancer TARGETases: DSB repair as a pharmacological target
Samadder, P., Aithal, R., Beláň, O., & Krejčí, L. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.02.007 · Cited by 31
TGFβ Promotes Genomic Instability after Loss of RUNX3
Krishnan, V., Chong, Y. L., Tan, T. Z., Kulkarni, M., Rahmat, M. B. B., Tay, L. S., Sankar, H., Jokhun, D. S., Ganesan, A., Chuang, L. S. H., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-1178 · Cited by 30
“molecular inhibitors, KU-55933 (10 M) and VE-821 (2 M), respectively (38,39).”
Therapeutic targeting of ATR in alveolar rhabdomyosarcoma
García, H. D., Pusch, F. F., Bei, Y., von Stebut, J., Ibáñez, G., Guillan, K. C., Imami, K., Gürgen, D., Rolff, J., Helmsauer, K., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32023-7 · Cited by 29

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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