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
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
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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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Triple-Negative Breast Cancer and Emerging Therapeutic Strategies: ATR and CHK1/2 as Promising Targets
Sofianidi, A. A., Dumbrava, E. E. I., Syrigos, K. N., & Nasrazadani, A. (2024) · Cancers · doi:10.3390/cancers16061139 · Cited by 31
“Interestingly, p53 deficient tumors demonstrate sensitivity to blockade by ATR or CHK1 inhibitors [67], positioning these agents as potentially attractive agents for the management of TNBC. BRCAness is a phenotype resembling mutations of germline BRCA1/2 DNA repair genes, which results in HRR…”
Background
The value of protein allostery in rational anticancer drug design: an update
Nussinov, R., & Jang, H. (2024) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2024.2384467 · Cited by 29
“…[84]), and exploiting p53 synthetic lethality with G 2 checkpoint inhibitor (e.g. CBP-93872 [85]) or deficiency with Wee1 inhibitors (e.g. adavoser-tib [86]) or with inhibitors of the DNA damage response, such as ATR (e.g. cisplatin [87]) and CHK1/2 (e.g. UCN-01 [88]) inhibitors (Figure 2).”
Targeting lung cancer through inhibition of checkpoint kinases
Syljuåsen, R. G., Hasvold, G., Hauge, S., & Helland, Å. (2015) · Frontiers in Genetics · doi:10.3389/fgene.2015.00070 · Cited by 29
“Another shared function of Chk1, Wee1, and ATR is their role in positive regulation of homologous recombination (HR) repair, a major pathway for repair of DNA double strand breaks.”
Background
Dual genome-wide CRISPR knockout and CRISPR activation screens identify mechanisms that regulate the resistance to multiple ATR inhibitors
Schleicher, E. M., Dhoonmoon, A., Clements, K. E., Jackson, L. M., Stump, C. L., Nicolae, C. M., & Moldovan, G. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1009176 · Cited by 31
XRCC1 deficient triple negative breast cancers are sensitive to ATR, ATM and Wee1 inhibitor either alone or in combination with olaparib
Ali, R., Alblihy, A., Toss, M. S., Algethami, M., Sunni, R. A., Green, A. R., Rakha, E. A., & Madhusudan, S. (2020) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758835920974201 · Cited by 28
Critical DNA damaging pathways in tumorigenesis
Kloeber, J. A., & Lou, Z. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.04.012 · Cited by 30
A Sterol-PI(4)P Exchanger Controls the Tel1/ATM Axis of the DNA Damage Response
Ovejero, S., Kumanski, S., Soulet, C., Azarli, J., Pardo, B., Santt, O., Constantinou, A., Pasero, P., & Moriel‐Carretero, M. (2022) · The EMBO Journal · doi:10.15252/embj.2022112684 · Cited by 24
“ATM and ATR act as parallel branches ensuring cell fitness, which underlies the basis of the lethality observed when combining ATM and ATR inhibitors (Reaper et al, 2011).”
Targeting the DNA damage response in cancer
Guffanti, F., Chiappa, M., & Damia, G. L. M. (2024) · MedComm · doi:10.1002/mco2.788 · Cited by 30
“Berzosertib is a potent ATP-competitive inhibitor of ATR/ATM with over > 100-fold selectivity over ATM, DNA-PKcs, and other PI3K α kinases 189 and strongly reduced the phosphorylation of Chk1, particularly in ATM/p53-deficient cell lines 190 .”
Background
Pharmacological targeting the ATR-CHK1–WEE1 axis involves balancing cell growth stimulation and apoptosis
Mak, J. P. Y., Man, W. Y., Ma, H. T., & Poon, R. Y. C. (2014) · Oncotarget · doi:10.18632/oncotarget.2508 · Cited by 27
“For example, ATRi (VE-821) was found to enhance the cytotoxicity caused by DNA damaging agents, particularly in cells with defective ATM and p53 [23].”
Background
Fibroblast Growth Factor 2 lethally sensitizes cancer cells to stress‐targeted therapeutic inhibitors
Dias, M. H., Fonseca, C. S., Zeidler, J. D., Albuquerque, L. L., da Silva, M. S., Lopes, E. C., Reis, M. S., Noël, V., dos Santos, E. O., Prior, I. A., et al. (2018) · Molecular Oncology · doi:10.1002/1878-0261.12402 · Cited by 26
Anti-Tumor Effect of Inhibition of DNA Damage Response Proteins, ATM and ATR, in Endometrial Cancer Cells
Takeuchi, M., Tanikawa, M., Nagasaka, K., Oda, K., Kawata, Y., Oki, S., Chuwa, A. H., Sone, K., Miyagawa, Y., Hiraike, H., et al. (2019) · Cancers · doi:10.3390/cancers11121913 · Cited by 30
ATR Inhibition Broadly Sensitizes Soft-Tissue Sarcoma Cells to Chemotherapy Independent of Alternative Lengthening Telomere (ALT) Status
Laroche‐Clary, A., Chaire, V., Verbeke, S., Algéo, M.-P., Malykh, A., Loarer, F. L., & Italiano, A. (2020) · Scientific Reports · doi:10.1038/s41598-020-63294-z · Cited by 27
Population pharmacokinetics of ATR inhibitor berzosertib in phase I studies for different cancer types
Terranova, N., Jansen, M., Falk, M., & Hendriks, B. S. (2020) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-020-04184-z · Cited by 29
Development of pharmacodynamic biomarkers for ATR inhibitors
Chen, T., Middleton, F. K., Falcon, S. C., Reaper, P. M., Pollard, J. R., & Curtin, N. J. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.09.012 · Cited by 30
Emerging targets for radioprotection and radiosensitization in radiotherapy
Kumar, S., Singh, R. K., & Meena, R. (2016) · Tumor Biology · doi:10.1007/s13277-016-5117-8 · Cited by 28
“VE-821, a novel ATR inhibitor has shown to synergistically enhance the effect of cisplatin in ATM or p53defective (H23) cell lines, while p53 wild-type normal fibroblast cell line (HFL1) remained unaffected [111].”
Background
SMCHD1 promotes ATM‐dependent DNA damage signaling and repair of uncapped telomeres
Vančevska, A., Ahmed, W., Pfeiffer, V., Feretzaki, M., Boulton, S. J., & Lingner, J. (2020) · The EMBO Journal · doi:10.15252/embj.2019102668 · Cited by 25
“For the experiment in Fig 4, ATRi (VE-821, Selleck-Chem, #S8007) was added to the cells 24 h after addition of the selection antibiotics at 10 l M concentration and the cells were maintained with the inhibitor for 4 days.”
Influential
The VRK1 chromatin kinase regulates the acetyltransferase activity of Tip60/KAT5 by sequential phosphorylations in response to DNA damage
García-González, R., Monte-Serrano, E., Morejón‐García, P., Navarro-Carrasco, E., & Lazo, P. A. (2022) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2022.194887 · Cited by 26
N-nitroso-N-ethylurea activates DNA damage surveillance pathways and induces transformation in mammalian cells
Bodakuntla, S., Anandi, L., V, Sural, S., Trivedi, P., & Lahiri, M. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-287 · Cited by 26
“To completely rule out cross-talk between the two canonical signalling pathways, VE 821, a potent ATP-competitive inhibitor of ATR [34] was added to cells prior to NEU treatment and a time-course assay was performed (Figure 3F).”
Method
Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment
Valikhani, M., Rahimian, E., Ahmadi, S. E., Chegeni, R., & Safa, M. (2021) · Experimental Hematology and Oncology · doi:10.1186/s40164-021-00242-1 · Cited by 26
Radiosensitization of Human Leukemic HL-60 Cells by ATR Kinase Inhibitor (VE-821): Phosphoproteomic Analysis
Šalovská, B., Fabrik, I., Ďurišová, K., Link, M., Vávrová, J., Řezáčová, M., & Tichý, A. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms150712007 · Cited by 26
“On the other hand, growth arrest induced by VE-821 in normal human lung fibroblasts (HFL-1) was fully reversible with minimal death [4].”
Background
Putting poly (ADP-ribose) polymerase and other DNA repair inhibitors into clinical practice
Helleday, T. (2013) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000016 · Cited by 27
TAS-116, a Novel Hsp90 Inhibitor, Selectively Enhances Radiosensitivity of Human Cancer Cells to X-rays and Carbon Ion Radiation
Lee, Y., Sunada, S., Hirakawa, H., Fujimori, A., Nickoloff, J. A., & Okayasu, R. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0573 · Cited by 26
FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B-cell acute leukemia
Ishizawa, J., Sugihara, E., Kuninaka, S., Mogushi, K., Kojima, K., Benton, C. B., Zhao, R., Chachad, D., Hashimoto, N., Jacamo, R. O., et al. (2017) · Blood · doi:10.1182/blood-2016-07-726216 · Cited by 25
Initial testing (stage 1) of M6620 (formerly VX‐970), a novel ATR inhibitor, alone and combined with cisplatin and melphalan, by the Pediatric Preclinical Testing Program
Kurmasheva, R. T., Kurmashev, D., Reynolds, C. P., Kang, M. H., Wu, J., Houghton, P. J., & Smith, M. A. (2017) · Pediatric Blood & Cancer · doi:10.1002/pbc.26825 · Cited by 27
Bimodal regulation of p21waf1protein as function of DNA damage levels
Buscemi, G., Ricci, C., Zannini, L., Fontanella, E., Plevani, P., & Delia, D. (2014) · Cell Cycle · doi:10.4161/15384101.2014.946852 · Cited by 25
Cells and Stripes: A novel quantitative photo-manipulation technique
Mistrík, M., Veselá, E., Fürst, T., Hanzlíková, H., Frydrych, I., Gurský, J., Majera, D., & Bártek, J. (2016) · Scientific Reports · doi:10.1038/srep19567 · Cited by 23
Sulfoximines as ATR inhibitors: Analogs of VE-821
Hendriks, C. M. M., Hartkamp, J., Wiezorek, S., Steinkamp, A., Rossetti, G., Lüscher, B., & Bolm, C. (2017) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2017.04.026 · Cited by 25
Double‐strand DNA breaks are mainly repaired by the homologous recombination pathway in early developing swine embryos
Bohrer, R. C., Dicks, N., Gutierrez, K., Duggavathi, R., & Bordignon, V. (2017) · The FASEB Journal · doi:10.1096/fj.201700800r · Cited by 25
Comparison of the different mechanisms of cytotoxicity induced by checkpoint kinase I inhibitors when used as single agents or in combination with DNA damage
Warren, N. J. H., & Eastman, A. R. (2019) · Oncogene · doi:10.1038/s41388-019-1079-9 · Cited by 27
“Oncogene-associated replication stress [22, 66] and loss of DNA damage response proteins [64, 65, 74, 75] have been reported to sensitize cells to ATRi, but again these defects do not correlate with sensitivity to CHK1i.”
Background
Beyond BRCA: The Emerging Significance of DNA Damage Response and Personalized Treatment in Pancreatic and Prostate Cancer Patients
Dalmasso, B., Puccini, A., Catalano, F., Borea, R., Iaia, M. L., Bruno, W., Fornarini, G., Sciallero, S., Rebuzzi, S. E., & Ghiorzo, P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094709 · Cited by 25
“Preclinical data showed the high activity of ATR-inhibitors (ATR-i) in tumors with a somatic mutation of the ATM pathway, since the ATM-deficient cells rely on the ATR pathway for survival [108,109].”
Background
A crucial role for ATR in the regulation of deoxycytidine kinase activity
Beyaert, M., Starczewska, E., Neste, E. V. D., & Bontemps, F. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.11.022 · Cited by 26
Randomized Phase II Study of Gemcitabine With or Without ATR Inhibitor Berzosertib in Platinum-Resistant Ovarian Cancer: Final Overall Survival and Biomarker Analyses
Konstantinopoulos, P. A., Cheng, S., Lee, E. K., da Costa, A. A. B. A., Gulhan, D., Hendrickson, A. E. W., Kochupurakkal, B. S., Kolin, D. L., Kohn, E. C., Liu, J. F., et al. (2024) · JCO Precision Oncology · doi:10.1200/po.23.00635 · Cited by 24
A Novel cytarabine analog evokes synthetic lethality by targeting MK2 in p53-deficient cancer cells
Song, J., Yu, J., Jeong, L. S., & Lee, S. K. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.10.003 · Cited by 24
Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes
Mavroeidi, D., Georganta, A., Panagiotou, Ε., Syrigos, K., & Souliotis, V. L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052767 · Cited by 26
“Importantly, VE-821 demonstrated a synergistic effect in tumor cells but not in normal cells [102].”
Background
Mutations in Replicative Stress Response Pathways Are Associated with S Phase-specific Defects in Nucleotide Excision Repair
Bélanger, F., Angers, J.-P., Fortier, É., Hammond-Martel, I., Costantino, S., Drobetsky, E., & Wurtele, H. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.685883 · Cited by 24
“C, HeLa cells were treated with VE-821 and mock- or UV-irradiated, as in A and B. Recruitment of RPA2 to chromatin after UV was detected by immunofluorescence microscopy.”
MethodInfluential
Hypoxia-Directed Drug Strategies to Target the Tumor Microenvironment
Hay, M. P., Hicks, K. O., & Wang, J. (2013) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-5915-6_6 · Cited by 24
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Nikolaev, A. Y., & Yang, E. S.-H. (2017) · Cancers · doi:10.3390/cancers9090126 · Cited by 24
Small-Molecule Screening for Genetic Diseases
Markossian, S., Ang, K. K. H., Wilson, C. G. M., & Arkin, M. R. (2018) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-083117-021452 · Cited by 24
Repurposing Ceritinib Induces DNA Damage and Enhances PARP Inhibitor Responses in High-Grade Serous Ovarian Carcinoma
Kanakkanthara, A., Hou, X., Ekstrom, T. L., Zanfagnin, V., Huehls, A. M., Kelly, R. L., Ding, H., Larson, M. C., Vasmatzis, G., Oberg, A. L., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-0732 · Cited by 23
Rewiring glucose metabolism improves 5-FU efficacy in p53-deficient/KRASG12D glycolytic colorectal tumors
Ludikhuize, M. C., Gevers, S., Nguyen, N. B., Meerlo, M., Roudbari, S. K. S., Gülersönmez, M. C., Stigter, E. C. A., Drost, J., Clevers, H. C., Burgering, B. M. T., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-04055-8 · Cited by 23
Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?
Goff, P. H., Bhakuni, R., Pulliam, T. H., Lee, J. H., Hall, E. T., & Nghiem, P. (2021) · Cancers · doi:10.3390/cancers13143415 · Cited by 23
The role of mediator subunit 12 in tumorigenesis and cancer therapeutics (Review)
Gonzalez, C., Akula, S., & Burleson, M. O. (2022) · Oncology Letters · doi:10.3892/ol.2022.13194 · Cited by 22
Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer
Ricciuti, B., Elkrief, A., Alessi, J. V., Wang, X., Li, Y. Y., Gupta, H. V., Muldoon, D. M., Bertram, A. A., Pecci, F., Lamberti, G., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-3413 · Cited by 22
Disease severity in a mouse model of ataxia telangiectasia is modulated by the DNA damage checkpoint gene Hus1
Balmus, G., Zhu, M., Mukherjee, S., Lyndaker, A. M., Hume, K. R., Lee, J., Riccio, M. L., Reeves, A. P., Sutter, N. B., Noden, D. M., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds173 · Cited by 22
“First, the synergistic increases in genome damage and apoptosis observed here following combined Atm and Hus1 impairment suggest that therapeutic targeting of HUS1 or the broader ATR pathway may be effective for some malignancies that arise due to ATM pathway mutations, which may be as many as 70% of all cancers (50,5…”
Background
Radiopotentiation Profiling of Multiple Inhibitors of the DNA Damage Response for Early Clinical Development
Gill, S. J., Wijnhoven, P. W. G., Fok, J. H. L., Lloyd, R. L., Cairns, J., Armenia, J., Nikkilä, J., Lau, A., Bakkenist, C. J., Galbraith, S. M., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0502 · Cited by 23
Inhibition of ATR-dependent feedback activation of Chk1 sensitises cancer cells to Chk1 inhibitor monotherapy
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Oncogenic RAS sensitizes cells to drug-induced replication stress via transcriptional silencing of P53
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“Interestingly, the lack of P53 can sensitize cells to ATR and CHK1 inhibition [20], suggesting a potential selection”
Background
Discovery of Thieno[3,2-d]pyrimidine derivatives as potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) kinase
Duan, Y., Cheng, H., Zhuang, L., Xia, J., Xu, Y., Zhang, R., Sun, R., Lu, T., & Chen, Y. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115370 · Cited by 22
Chemical strategies for development of ATR inhibitors
Llona‐Minguez, S., Höglund, A., Jacques, S. A., Koolmeister, T., & Helleday, T. (2014) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2014.10 · Cited by 22
Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia
Pouliot, G. P., Degar, J., Hinze, L., Kochupurakkal, B. S., Vo, C. D., Burns, M., Moreau, L. A., Ganesa, C., Roderick, J. E., Peirs, S., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0221288 · Cited by 21
“To confirm these findings, we then treated our two independent BRCA2 haploinsufficient clones with either VE-821 or the structurally distinct ATR inhibitor AZD6738 [54], and found that ATR inhibition exhibits sustained differential toxicity to BRCA2 haploinsufficient Jurkat T-ALL cells (Fig 5B and 5C).”
BackgroundInfluential
Regulation of Rad17 Protein Turnover Unveils an Impact of Rad17-APC Cascade in Breast Carcinogenesis and Treatment*
Zhou, Z., Jing, C., Zhang, L., Fujita, T., Kim, H., Huang, Y., Liu, Z., & Wan, Y. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.456962 · Cited by 21
TIPIN depletion leads to apoptosis in breast cancer cells
Baldeyron, C., Brisson, A., Tesson, B. M., Némati, F., Koundrioukoff, S., Saliba, E., de Koning, L., Martel, E., Ye, M., Rigaill, G. J., et al. (2015) · Molecular Oncology · doi:10.1016/j.molonc.2015.04.010 · Cited by 23
“Other studies have shown that TIPIN and TIM are under-expressed in kidney (Mazzoccoli et al., 2012) and pancreatic (Relles et al., 2013) cancers.”
Result
Targeting the CINful genome: Strategies to overcome tumor heterogeneity
Cunningham, C. E., MacAuley, M. J., Yadav, G., Vizeacoumar, F. S., Freywald, A., & Vizeacoumar, F. J. (2019) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2019.02.006 · Cited by 19
The interplay of TARG1 and PARG protects against genomic instability
Groslambert, J., Prokhorova, E. A., Wondisford, A. R., Tromans‐Coia, C., Giansanti, C., Jansen, J., Timinszky, G., Dobbelstein, M., Ahel, D., O’Sullivan, R. J., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113113 · Cited by 21
Elimusertib has Antitumor Activity in Preclinical Patient-Derived Pediatric Solid Tumor Models
Pusch, F. F., García, H. D., Xu, R., Gürgen, D., Bei, Y., Brückner, L., Röefzaad, C., von Stebut, J., Bardinet, V., González, R. C., et al. (2023) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-23-0094 · Cited by 25
Simultaneous inhibition of ATR and PARP sensitizes colon cancer cell lines to irinotecan
Abusanad, A. M., Wang, Y., Hasheminasab, F., Panasci, J., Noë, A., Rosca, L., Davidson, D. L., Amrein, L., Sharif-Askari, B., Aloyz, R. S., et al. (2015) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00147 · Cited by 20
The ATR Signaling Pathway Is Disabled during Infection with the Parvovirus Minute Virus of Mice
Adeyemi, R. O., & Pintel, D. J. (2014) · Journal of Virology · doi:10.1128/jvi.01412-14 · Cited by 20
Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation
Vendetti, F. P., Leibowitz, B. J., Barnes, J., Schamus, S., Kiesel, B. F., Abberbock, S. R., Conrads, T. P., Clump, D. A., Cadogan, E. B., O’Connor, M. J., et al. (2017) · Scientific Reports · doi:10.1038/srep41892 · Cited by 21
Regulation of ATR activity via the RNA polymerase II associated factors CDC73 and PNUTS-PP1
Landsverk, H. B., Sandquist, L. E., Sridhara, S. R. C., Rødland, G. E., Sabino, J. C., de Almeida, S. F., Grallert, B., Trinkle‐Mulcahy, L., & Syljuåsen, R. G. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky1233 · Cited by 24
“As CHK1 and RPA32 are ATR targets (33,34), we addressed whether ATR signaling was affected specifically.”
From yeast to humans: Understanding the biology of DNA Damage Response (DDR) kinases
Cussiol, J. R. R., Soares, B. L., & de Oliveira, F. M. B. (2019) · Genetics and Molecular Biology · doi:10.1590/1678-4685-gmb-2019-0071 · Cited by 21
“Therefore, pharmacological inhibition of ATR selectively sensitizes different types of tumor cells, especially in tumors with defects in the ATM-p53 pathway (Charrier et al., 2011; Peasland et al., 2011; Reaper et al., 2011; Toledo et al., 2011b; Fokas et al., 2012; Foote et al., 2013, 2015,2018; Kim et al., 2018).”
Background
Poly(ADP-Ribose) Polymerase Inhibitors in Prostate Cancer: Molecular Mechanisms, and Preclinical and Clinical Data
Sigorski, D., Iżycka‐Świeszewska, E., & Bodnar, L. (2020) · Targeted Oncology · doi:10.1007/s11523-020-00756-4 · Cited by 21
“ATR, CHEK1) are also being investigated as new therapeutic targets [53, 54].”
Background
Genome integrity and neurogenesis of postnatal hippocampal neural stem/progenitor cells require a unique regulator Filia
Li, J., Shang, Y., Wang, L., Zhao, B., Sun, C., Li, J., Liu, S., Li, C., Tang, M., Meng, F., et al. (2020) · Science Advances · doi:10.1126/sciadv.aba0682 · Cited by 20
“S5, B and C) ( 27 ).”
Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics
Sharma, R. L., Mishra, A., Bhardwaj, M., Singh, G., Harahap, L. V. I., Vanjani, S., Pan, C., & Nepali, K. (2025) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2025.2489720 · Cited by 20
YU238259 Is a Novel Inhibitor of Homology-Dependent DNA Repair That Exhibits Synthetic Lethality and Radiosensitization in Repair-Deficient Tumors
Stachelek, G. C., Peterson-Roth, E., Liu, Y., Fernandez, R. J., Pike, L., Qian, J. M., Abriola, L., Hoyer, D., Hungerford, W. M., Merkel, J., et al. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0036 · Cited by 19
Synthetic lethality: the road to novel therapies for breast cancer
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ATM Is Required for the Repair of Oxaliplatin-Induced DNA Damage in Colorectal Cancer
Bakkenist, C. J., Lee, J. J., & Schmitz, J. C. (2018) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2018.09.001 · Cited by 19
Human CTC1 promotes TopBP1 stability and CHK1 phosphorylation in response to telomere dysfunction and global replication stress
Ackerson, S. M., Gable, C. I., & Stewart, J. A. (2020) · Cell Cycle · doi:10.1080/15384101.2020.1849979 · Cited by 18
Novel caffeine derivatives with antiproliferative activity
Andrš, M., Muthná, D., Řezáčová, M., Seifrtová, M., Šiman, P., Korábečný, J., Benek, O., Doležal, R., Soukup, O., Jun, D., et al. (2016) · RSC Advances · doi:10.1039/c5ra22889a · Cited by 20
Ataxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types
Pilie, P. G., Giuliani, V., Wang, W., McGrail, D. J., Bristow, C. A., Ngoi, N. Y. L., Kyewalabye, K., Wani, K., Le, H., Campbell, E., et al. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-1763 · Cited by 20
Discovery of ART0380, a Potent and Selective ATR Kinase Inhibitor Undergoing Phase 2 Clinical Studies for the Treatment of Advanced or Metastatic Solid Cancers
Carroll, C. L., Johnson, M. G., Ding, Y., Kang, Z., Vijayan, R. S. K., Bardenhagen, J., Fang, C., Lapointe, D. S., Li, M., Liu, C.-Y., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01595 · Cited by 18
The molecular landscape of pancreatic ductal adenocarcinoma
Sivapalan, L., Kocher, H. M., Ross‐Adams, H., & Chelala, C. (2022) · Pancreatology · doi:10.1016/j.pan.2022.07.010 · Cited by 21
Discovery of novel 7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidines as ATR inhibitors based on structure-based drug design
Qi, Y., Wang, K., Long, B., Yue, H., Wu, Y., Yang, D., Tong, M., Shi, X., Hou, Y., & Zhao, Y. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114945 · Cited by 21
Metabolic clogging of mannose triggers dNTP loss and genomic instability in human cancer cells
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Programmable DNA Hydrogel Assisting Microcrystal Formulations for Sustained Locoregional Drug Delivery in Surgical Residual Tumor Lesions and Lymph Node Metastasis
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Therapeutic targeting of the DNA damage response in prostate cancer
Marshall, C. H., & Antonarakis, E. S. (2020) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000617 · Cited by 17
“There is early preclinical evidence that synthetic lethality can be achieved in cancers with ATM mutations by treatment with ATR inhibitors [32,33].”
Background
ZEB1 inhibition sensitizes cells to the ATR inhibitor VE-821 by abrogating epithelial–mesenchymal transition and enhancing DNA damage
Song, N., Jing, W., Li, C., Bai, M., Cheng, Y., Li, H., Hou, K., Li, Y., Wang, K., Li, Z., et al. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1404206 · Cited by 17
“In 2011, the first potent and selective inhibitor, VE821, was finally reported [5].”
Background
Distinct cellular responses to replication stress leading to apoptosis or senescence
Lukášová, E., Řezáčová, M., Bačı́ková, A., Šebejová, L., Vávrová, J., & Kozubek, S. (2019) · FEBS Open Bio · doi:10.1002/2211-5463.12632 · Cited by 17
p53-dependent crosstalk between DNA replication integrity and redox metabolism mediated through a NRF2-PARP1 axis
Elfar, G. A., Aning, O. A., Ngai, T. W., Yeo, P., Chan, J. W. K., Sim, S. H., Goh, L., Ju, Y., Phua, C. Z. J., Yeo, J. Z. Z., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae811 · Cited by 17
“Given the established but not fully elucidated synergism between deficiencies in p53 and ATR ( 45 ,102 ), we hypothesize that p53 plays a critical role in preserving fork integrity, particularly when forks are rendered vulnerable due to ATR inhibition.”
Background
ERβ Sensitizes NSCLC to Chemotherapy by Regulating DNA Damage Response
Nikolos, F., Thomas, C. G., Bado, I. L., & Gustafsson, J.-Α. (2017) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-17-0201 · Cited by 17
“The absence of functional p53 protein alters the DNA damage response of cancer cells and strategies have been developed to target p53-defective tumors (56).”
Background
Early TP53 Alterations Shape Gastric and Esophageal Cancer Development
Sahgal, P., Huffman, B. M., Patil, D. T., Chatila, W. K., Yaeger, R. D., Cleary, J. M., & Sethi, N. S. (2021) · Cancers · doi:10.3390/cancers13235915 · Cited by 17
Functional analyses of ATM, ATR and Fanconi anemia proteins in lung carcinoma
Beumer, J. H., Fu, K. Y., Anyang, B. N., Siegfried, J. M., & Bakkenist, C. J. (2015) · BMC Cancer · doi:10.1186/s12885-015-1649-3 · Cited by 17
“This contrasts with a recent report that shows synergy between carboplatin and ATR kinase inhibitor ETP-46464 in ovarian cancer cell lines [26] and data that documents synergy between carboplatin and another ATR kinase inhibitor [17].”
Discovery of small-molecule ATR inhibitors for potential cancer treatment: a patent review from 2014 to present
Hu, S., Hui, Z., Duan, J., Garrido, C., Xie, T., & Ye, X. (2022) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2022.2027911 · Cited by 16
ATR represents a therapeutic vulnerability in clear cell renal cell carcinoma
Seidel, P., Rubarth, A., Zodel, K., Peighambari, A., Neumann, F., Federkiel, Y., Huang, H., Hoefflin, R., Adlesic, M., Witt, C. C., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.156087 · Cited by 16
“Similar synergies between ATR inhibitors and chemotherapeutic agents have been identified in other cancer cell types (39, 45).”
Background
NEK 6‐mediated phosphorylation of human TPP 1 regulates telomere length through telomerase recruitment
Hirai, Y., Tamura, M., Otani, J., & Ishikawa, F. (2016) · Genes to Cells · doi:10.1111/gtc.12391 · Cited by 17
“…to Cells (2016) 21, 874–889 © 2016 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd874 Genes to Cells OB-fold domain of TPP1 comprises an interaction interface with telomerase (Nandakumar et al. 2012; Sexton et al. 2012; Zhong et al. 2012; Schmidt et al. 2014).”
Background
PD-L1 upregulation accompanied with epithelial–mesenchymal transition attenuates sensitivity to ATR inhibition in p53 mutant pancreatic cancer cells
Song, N., Bai, M., Che, X., Li, Z., Jing, W., Li, C., Teng, Z., Qu, X., & Liu, Y. (2020) · Medical Oncology · doi:10.1007/s12032-020-01372-y · Cited by 16
“by its downstream target checkpoint kinase 1(Chk1) [5, 6].”
BackgroundInfluential
ATR Inhibitors in Platinum-Resistant Ovarian Cancer
Li, S., Wang, T., Fei, X., & Zhang, M. (2022) · Cancers · doi:10.3390/cancers14235902 · Cited by 16
“[52] reported that VE-821 significantly enhanced the sensitivity of OC cell lines with BRCA deficiency to veliparib (a kind of PARPi).”
Background
A quasi-quantitative dual multiplexed immunoblot method to simultaneously analyze ATM and H2AX phosphorylation in human peripheral blood mononuclear cells
Bakkenist, C. J., Czambel, R. K., Hershberger, P. A., Tawbi, H. A.-H., Beumer, J. H., & Schmitz, J. C. (2015) · Oncoscience · doi:10.18632/oncoscience.162 · Cited by 16
“To this end, pharmacologic inhibitors of the apurinic/apyrimidinic endonuclease-1 (APE1) and poly(ADP-ribose) polymerase (PARP), enzymes essential for base excision repair (BER), ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR), DNA damage signaling kinases that mediate homologous r…”
Background
Selective human inhibitors of ATR and ATM render Leishmania major promastigotes sensitive to oxidative damage
da Silva, R. B., Machado, C. R., Rodrigues, A. R. A., & Pedrosa, A. L. (2018) · PLoS ONE · doi:10.1371/journal.pone.0205033 · Cited by 16
Synergistic anticancer activity of combined ATR and ribonucleotide reductase inhibition in Ewing's sarcoma cells
Sturm, M.-J., Henao-Restrepo, J. A., Becker, S., Proquitté, H., Beck, J. F., & Sonnemann, J. (2023) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-023-04804-0 · Cited by 16
“VE821 was developed as a selective ATRi (Reaper et al. 2011), and its clinical formulation berzosertib (also known as VE822, VX970 and M6620) is being tested in several phase I and II clinical”
Background
Mapping combinatorial drug effects to DNA damage response kinase inhibitors
Zhang, H., Kreis, J., Schelhorn, S.-E., Dahmen, H., Grombacher, T., Zühlsdorf, M., Zenke, F. T., & Guan, Y. (2023) · Nature Communications · doi:10.1038/s41467-023-44108-y · Cited by 15
ATR suppresses apoptosis after UVB light by controlling both translesion synthesis and alternative tolerance pathways
de Andrade-Lima, L. C., Andrade, L. N. D. S., & Menck, C. F. M. (2014) · Journal of Cell Science · doi:10.1242/jcs.161596 · Cited by 15
“, 2007) and is growing as a potential sensitizer of chemotherapy or radiation, with selective killing of p53-deficient cancer cells (Reaper et al., 2011; Peasland et al., 2011; Prevo et al., 2012; Sultana et al., 2013).”
Background
Breaking the DNA Damage Response via Serine/Threonine Kinase Inhibitors to Improve Cancer Treatment
Rozpędek‐Kamińska, W., Pytel, D., Nowak-Zduńczyk, A., Lewko, D., Wojtczak, R., Diehl, J. A., & Majsterek, I. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666180117102233 · Cited by 15
Opportunities for Utilization of DNA Repair Inhibitors in Homologous Recombination Repair-Deficient and Proficient Pancreatic Adenocarcinoma
Cleary, J. M., Wolpin, B. M., Dougan, S. K., Raghavan, S., Singh, H., Huffman, B. M., Sethi, N. S., Nowak, J. A., Shapiro, G. I., Aguirre, A. J., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-1367 · Cited by 16
PCNA-Ub polyubiquitination inhibits cell proliferation and induces cell-cycle checkpoints
Qin, Z., Bai, Z., Sun, Y. J., Niu, X., & Xiao, W. (2016) · Cell Cycle · doi:10.1080/15384101.2016.1245247 · Cited by 16
Science in Focus: Combining Radiotherapy with Inhibitors of the DNA Damage Response
Chalmers, A. J. (2016) · Clinical Oncology · doi:10.1016/j.clon.2016.01.035 · Cited by 15
“As with ATM inhibitors, a number of studies have indicated that the effects of ATR or Wee1 inhibitors are more pronounced in p53 defective contexts [18,19].”
Background
Design, synthesis, and biological evaluation of pyrido[3,2-d]pyrimidine derivatives as novel ATR inhibitors
Duan, Y., Zhuang, L., Xu, Y., Cheng, H., Xia, J., Lu, T., & Chen, Y. (2023) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2023.106535 · Cited by 14
Discovery of Preclinical Candidate AD1058 as a Highly Potent, Selective, and Brain-Penetrant ATR Inhibitor for the Treatment of Advanced Malignancies
Liu, Z., Jiang, K., Liu, Y., Li, J., Huang, S., Li, P., Xu, L., Xu, X., Hu, X., Zeng, X., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00734 · Cited by 14
Mutation of Serine 1333 in the ATR HEAT Repeats Creates a Hyperactive Kinase
Luzwick, J. W., Nam, E. A., Zhao, R., & Cortez, D. (2014) · PLoS ONE · doi:10.1371/journal.pone.0099397 · Cited by 14
Differential Effect of Schisandrin B Stereoisomers on ATR-Mediated DNA Damage Checkpoint Signaling
Tatewaki, N., Nishida, H., Yoshida, M., Ando, H., Kondo, S., Sakamaki, T., & Konishi, T. (2013) · Journal of Pharmacological Sciences · doi:10.1254/jphs.13048fp · Cited by 14
G1/S and G2/M Cyclin-Dependent Kinase Activities Commit Cells to Death in the Absence of the S-Phase Checkpoint
Manfrini, N., Gobbini, E., Baldo, V., Trovesi, C., Lucchini, G., & Longhese, M. P. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00956-12 · Cited by 15
“This finding is complementary to earlier observations in mammalian systems, where ATR and Chk1 inhibitors were shown to be particularly toxic for p53-deficient cells, which lack the G1 checkpoint and therefore experience a less restrictive S-phase entry in the presence of DNA damage (42, 57).”
Result

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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