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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Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress
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ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response
Blackford, A. N., & Jackson, S. P. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.05.015 · Cited by 2,050
DNA Damage Sensing by the ATM and ATR Kinases
Marechal, A., & Zou, L. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a012716 · Cited by 1,514
“More recently, ATR-specific inhibitors have also become available and were shown to enhance the sensitivity of cancer cells to cisplatin and irradiation (Charrier et al. 2011; Reaper et al. 2011; Pires et al. 2012).”
Background
Targeting the DNA Damage Response in Cancer
O’Connor, M. J. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.10.040 · Cited by 1,602
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Targeting DNA Repair in Cancer: Beyond PARP Inhibitors
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“Beyond PARP inhibitors, preclinical data have demonstrated synergy between ATR inhibition and impaired ATM signaling, particularly in the context of exogenous DNA damage (119).”
Background
Targeting mutant p53 for cancer therapy: direct and indirect strategies
Hu, J., Cao, J., Topatana, W., Juengpanich, S., Li, S., Zhang, B., Shen, J., Cai, L., Cai, X., & Chen, M. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01169-0 · Cited by 569
Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors
Flynn, R. L., Cox, K. E., Jeitany, M., Wakimoto, H., Bryll, A. R., Ganem, N. J., Bersani, F., Pineda, J. R., Suvà, M. L., Benes, C. H., et al. (2015) · Science · doi:10.1126/science.1257216 · Cited by 514
Synthetic Lethality and Cancer Therapy: Lessons Learned from the Development of PARP Inhibitors
Lord, C. J., Tutt, A. N. J., & Ashworth, A. (2014) · Annual Review of Medicine · doi:10.1146/annurev-med-050913-022545 · Cited by 493
ATM Mutations in Cancer: Therapeutic Implications
Choi, M. P., Kipps, T. J., & Kurzrock, R. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0945 · Cited by 475
ATR phosphorylates SMARCAL1 to prevent replication fork collapsePreprint
Couch, F. B., Bansbach, C. E., Driscoll, R., Luzwick, J. W., Glick, G. G., Betous, R., Carroll, C. M., Jung, S. Y., Qin, J., Cimprich, K. A., et al. (2013) · Genes & Development · doi:10.1101/gad.214080.113 · Cited by 440
“This concentration did not inhibit ATM, DNA-PKcs, or mTOR kinases (Reaper et al. 2011; data not shown). siRNA transfections were performed using either HiPerfect (Qiagen) or Dharmafect 1 (Dharmacon) at a final siRNA concentration of 10 nM. siRNAs were purchased from Dharmacon or Ambion.”
BackgroundMethod
ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A
Williamson, C. T., Miller, R., Pemberton, H. N., Jones, S. E., Campbell, J., Konde, A., Badham, N., Rafiq, R., Brough, R., Gulati, A., et al. (2016) · Nature Communications · doi:10.1038/ncomms13837 · Cited by 382
Self-citation
ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cellsPreprint
Yazinski, S. A., Comaills, V., Buisson, R., Genois, M., Nguyen, H. D., Ho, C. K., Kwan, T. T., Morris, R. T., Lauffer, S., Nussenzweig, A., et al. (2017) · Genes & Development · doi:10.1101/gad.290957.116 · Cited by 405
“In cell-free assays, inhibitors of ATM (ATMi: KU55933), ATR (ATRi: VE-821), and DNA-PK (DNA-PKi: NU7026) all have IC50s in the 10 – 100 nM range (Hollick et al. 2003; Hickson et al. 2004; Reaper et al. 2011).”
RAD52 Facilitates Mitotic DNA Synthesis Following Replication Stress
Bhowmick, R., Minocherhomji, S., & Hickson, I. D. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.10.037 · Cited by 398
“This strategy is currently in clinical trials as a potential anti-cancer therapy (Reaper et al., 2011; Toledo et al., 2011).”
Background
The Replication Checkpoint Prevents Two Types of Fork Collapse without Regulating Replisome Stability
Dungrawala, H., Rose, K. L., Bhat, K. P., Mohni, K. N., Glick, G. G., Couch, F. B., & Cortez, D. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.07.030 · Cited by 395
“…hyper-recruitment of ATM to forks in ATR-inhibited cells is consistent with the synthetic lethality relationship between these kinases (Mohni et al., 2014; Reaper et al., 2011), and it also may explain the small increase in CHK1 phosphorylation at later times in the ATRi-treated cells (Figure S1B).”
Background
Targeting replication stress in cancer therapy
da Costa, A. A. B. A., Chowdhury, D., Shapiro, G. I., D’Andrea, A. D., & Konstantinopoulos, P. A. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00558-5 · Cited by 380
ATR/CHK1 inhibitors and cancer therapy
Qiu, Z., Oleinick, N. L., & Zhang, J. (2017) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2017.09.043 · Cited by 390
Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation
Fokas, E., Prevo, R., Pollard, J. R., Reaper, P. M., Charlton, P., Cornelissen, B. T., Vallis, K. A., Hammond, E. M., Olcina, M. M., McKenna, W. G., et al. (2012) · Cell Death and Disease · doi:10.1038/cddis.2012.181 · Cited by 378
“(Rahway, NJ, USA)(45) Tumor cells, normal human fibroblast cells (MRC5: CCL-171; and HFL-1: CCL-153) and the primary PDAC line (PancM; passage 17) were obtained and cultured as previously described.(15,31,46) HDMECs (Lonza, Slough, UK) were cultured as reported.”
BackgroundMethodInfluential
Targeting ATR in cancer
Lecona, E., & Fernández-Capetillo, Ó. (2018) · Nature reviews. Cancer · doi:10.1038/s41568-018-0034-3 · Cited by 341
DNA damage checkpoint kinases in cancer
Smith, H. L., Southgate, H. E. D., Tweddle, D. A., & Curtin, N. J. (2020) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2020.3 · Cited by 328
Distinct but Concerted Roles of ATR, DNA-PK, and Chk1 in Countering Replication Stress during S Phase
Buisson, R., Boisvert, J. L., Benes, C. H., & Zou, L. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.07.029 · Cited by 316
“Acute ATR Inactivation Leads to Two Distinct Outcomes in S-Phase Cells To investigate how ATR functions in cycling cells, we acutely inactivated ATR in U2OS cells with the ATRi VE-821 and followed the effects over time (Figures S1A and S1B; Reaper et al., 2011).”
Exploiting replicative stress to treat cancer
Dobbelstein, M., & Sørensen, C. S. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4553 · Cited by 309
Polyubiquitinated PCNA Recruits the ZRANB3 Translocase to Maintain Genomic Integrity after Replication Stress
Ciccia, A., Nimonkar, A. V., Hu, Y., Hajdú, I., Achar, Y. J., Izhar, L., Petit, S. A., Adamson, B., Yoon, J. C., Kowalczykowski, S. C., et al. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.05.024 · Cited by 308
Targeting the ATR/CHK1 Axis with PARP Inhibition Results in Tumor Regression in BRCA -Mutant Ovarian Cancer Models
Kim, H., George, E. M., Ragland, R. L., Rafail, S., Zhang, R., Krepler, C., Morgan, M. A., Herlyn, M., Brown, E. J., & Simpkins, F. A. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2273 · Cited by 304
“Almost all HGSOCs harbor a mutation in TP53 (2) and thus have lost G1 checkpoint control, significantly increasing reliance on S and G2 checkpoints for survival (11, 18).”
Background
ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells
Kwok, M., Davies, N., Agathanggelou, A., Smith, E., Oldreive, C., Petermann, E., Stewart, G. S., Brown, J., Lau, A., Pratt, G., et al. (2015) · Blood · doi:10.1182/blood-2015-05-644872 · Cited by 288
DNA Damage Response: Three Levels of DNA Repair Regulation
Sirbu, B. M., & Cortez, D. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a012724 · Cited by 272
“The development of new reversible ATR inhibitors (Charrier et al. 2011; Reaper et al. 2011; Toledo et al. 2011), as well as new techniques to study DNA replication such as iPOND should accelerate the mechanistic studies (Sirbu et al.”
Background
Molecular Pathways: Targeting ATR in Cancer Therapy
Karnitz, L. M., & Zou, L. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0479 · Cited by 274
“Second, ATM deficiency renders cells far more sensitive to ATR inhibition in cell culture and in animal models (25-27), a finding that has led to clinical trials of an ATR inhibitor in tumors characterized by ATM deficiency or ATM mutations (see below).”
Background
PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells
Quinet, A., Tirman, S., Jackson, J., Šviković, S., Lemacon, D. S., Carvajal-Maldonado, D., González‐Acosta, D., Vessoni, A. T., Cybulla, E., Wood, M. D., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.10.008 · Cited by 273
The Colibactin Genotoxin Generates DNA Interstrand Cross-Links in Infected Cells
Bossuet‐Greif, N., Vignard, J., Taieb, F. E., Mirey, G., Dubois, D., Petit, C. R., Oswald, É., & Nougayrède, J. (2018) · mBio · doi:10.1128/mbio.02393-17 · Cited by 281
“Inactivating ATR by the use of its specific inhibitor VE-821 (ATRi) (41) prevented this response (Fig.”
Background
Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors
Yap, T. A., O’Carrigan, B., Penney, M. S., Lim, J. S. J., Brown, J. S., Miguel, M. J. D., Tunariu, N., Pérez-López, R., Rodrigues, D. N., Riisnaes, R., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.19.02404 · Cited by 257
“The rationale for the trial comes from extensive preclinical studies demonstrating that ATR inhibition lethally sensitizes many cancer cells to DNA-damaging chemotherapies, including carboplatin, and that ATR inhibition can be effective as monotherapy in cancer cells with aberrations that impair alternative repair pat…”
BackgroundInfluential
Molecular Pathways: Overcoming Radiation Resistance by Targeting DNA Damage Response Pathways
Morgan, M. A., & Lawrence, T. S. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-3229 · Cited by 252
“For example, ATM-defective cancers are particularly susceptible to DNA-PK or ATR inhibition (19, 20).”
Background
PRP19 Transforms into a Sensor of RPA-ssDNA after DNA Damage and Drives ATR Activation via a Ubiquitin-Mediated Circuitry
Maréchal, A., Li, J.-M., Ji, X. Y., Wu, C.-S. P., Yazinski, S. A., Nguyen, H. D., Liu, S., Jiménez, A. E., Jin, J., & Zou, L. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.11.002 · Cited by 258
“On the other hand, VE-821, a specific inhibitor of ATR (Reaper et al., 2011), clearly diminished the CPTinduced PRP19-RPA interaction in cells (Fig.”
Identification of Proteins at Active, Stalled, and Collapsed Replication Forks Using Isolation of Proteins on Nascent DNA (iPOND) Coupled with Mass Spectrometry
Sirbu, B. M., McDonald, W. H., Dungrawala, H., Badu-Nkansah, A., Kavanaugh, G. M., Chen, Y., Tabb, D. L., & Cortez, D. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.511337 · Cited by 251
“To identify proteins associated with fork collapse, cells were treated with hydroxyurea and a selective ATR inhibitor (10) for 2 h.”
Method
The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy
Prevo, R., Fokas, E., Reaper, P. M., Charlton, P., Pollard, J. R., McKenna, W. G., Muschel, R. J., & Brunner, T. B. (2012) · Cancer Biology & Therapy · doi:10.4161/cbt.21093 · Cited by 251
The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancerin vivo
Vendetti, F. P., Lau, A., Schamus, S., Conrads, T. P., O’Connor, M. J., & Bakkenist, C. J. (2015) · Oncotarget · doi:10.18632/oncotarget.6247 · Cited by 252
“Increased ATM kinase activity in cells treated with ATR kinase inhibitors has been reported previously [23, 26].”
BackgroundResult
Targeting the ATR-CHK1 Axis in Cancer Therapy
Rundle, S., Bradbury, A., Drew, Y., & Curtin, N. J. (2017) · Cancers · doi:10.3390/cancers9050041 · Cited by 242
“The first truly selective ATR inhibitor, VE-821, showed synergy with gemcitabine in human colon cancer cell lines [81].”
BackgroundInfluential
Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial
Konstantinopoulos, P. A., Cheng, S., Hendrickson, A. E. W., Penson, R. T., Schumer, S., Doyle, L. A., Lee, E. K., Kohn, E. C., Duska, L., Crispens, M. A., et al. (2020) · The Lancet Oncology · doi:10.1016/s1470-2045(20)30180-7 · Cited by 229
The Meaning, Measurement and Modification of Hypoxia in the Laboratory and the Clinic
Hammond, E. M., Asselin, M., Forster, D. M., O’Connor, J. P. B., Senra, J. M., & Williams, K. J. (2014) · Clinical Oncology · doi:10.1016/j.clon.2014.02.002 · Cited by 227
“Recent studies using potent and specific inhibitors of cellular ATR activity, such as VE-821 and VE-822, showed promise in sensitising a variety of cancer cells to a range of oxygen concentrations [37,47,48].”
Background
Failure of Iniparib to Inhibit Poly(ADP-Ribose) Polymerase In Vitro
Patel, A. G., Lorenzo, S. B. D., Flatten, K. S., Poirier, G. G., & Kaufmann, S. H. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2890 · Cited by 213
“5B) as previously reported (34), indicating that sensitization by iniparib could have been observed if present.”
The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage–Inducing or Repair–Compromising Therapies in Preclinical Cancer Models
Wengner, A. M., Siemeister, G., Lücking, U., Lefranc, J., Wortmann, L., Lienau, P., Bader, B., Bömer, U., Moosmayer, D., Eberspächer, U., et al. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0019 · Cited by 208
“As ionizing radiation also causes an extensive amount of less cytotoxic DNA lesions, such as DNA single-strand breaks (SSBs) (45), recent research has focused on the radio-sensitization of tumors by combining radiation with DDR-targeted agents, and these studies have demonstrated promising preclinical efficacy (25,46-…”
Background
ATM signalling and cancer
Cremona, C. A., & Behrens, A. (2013) · Oncogene · doi:10.1038/onc.2013.275 · Cited by 219
ATR Inhibition Broadly Sensitizes Ovarian Cancer Cells to Chemotherapy Independent of BRCA Status
Huntoon, C. J., Flatten, K. S., Hendrickson, A. E. W., Huehls, A. M., Sutor, S. L., Kaufmann, S. H., & Karnitz, L. M. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-0110 · Cited by 209
“Previous studies showed that MK-8776 and other Chk1 inhibitors block Chk1 autophosphorylation on Ser(296) (38, 46–48) and that VE-821 abrogates ATR-mediated Chk1 Ser(345) phosphorylation (21), suggesting that these phosphorylation events may provide an effective way to assess Figure 5.”
BackgroundInfluential
A Genome-wide CRISPR Screen Identifies CDC25A as a Determinant of Sensitivity to ATR Inhibitors
Ruiz, S., Mayor‐Ruiz, C., Lafarga, V., Murga, M., Vega-Sendino, M., Ortega, S., & Fernández-Capetillo, Ó. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.03.006 · Cited by 202
“Accordingly, mice with reduced ATR levels are refractory to the development of various tumors (Murga et al., 2011; Schoppy et al., 2012), and ATR inhibitors are preferentially toxic for cells expressing MYC or CYCE oncogenes, or lacking tumor suppressors such as ATM or P53 (Kwok et al., 2015; Reaper et al., 2011; Tole…”
BackgroundInfluential
Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970
Hall, A. B., Newsome, D., Wang, Y., Boucher, D. M., Eustace, B. K., Gu, Y., Hare, B. J., Johnson, M., Li, H. Y., Milton, S., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.2158 · Cited by 204
“This has been attributed to a synthetic lethal relationship between the ATR and ATM signaling pathways[8, 14-17, 19].”
BackgroundMethodInfluential
ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation
Vendetti, F. P., Karukonda, P., Clump, D. A., Teo, T., Lalonde, R., Nugent, K., Ballew, M., Kiesel, B. F., Beumer, J. H., Sarkar, S. N., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci96519 · Cited by 198
Translating p53-based therapies for cancer into the clinic
Peuget, S., Zhou, X., & Selivanova, G. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-023-00658-3 · Cited by 208
Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines
Peasland, A., Wang, L.-Z., Rowling, E. J., Kyle, S., Chen, T., Hopkins, A. P., Cliby, W. A., Sarkaria, J. N., Beale, G., Edmondson, R. J., et al. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.243 · Cited by 202
“Similarly, the recently identified inhibitor VE-821 enhanced the cytotoxicity of cisplatin, gemcitabine, camptothecin etoposide and IR, but not docetaxel in HCT 116 colon cancer cells (Reaper et al, 2011).”
Background
Targeting ATR in DNA damage response and cancer therapeutics
Fokas, E., Prevo, R., Hammond, E. M., Brunner, T. B., McKenna, W. G., & Muschel, R. J. (2013) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2013.03.002 · Cited by 197
Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells
Ohashi, A., Ohori, M., Iwai, K., Nakayama, Y., Nambu, T., Morishita, D., Kawamoto, T., Miyamoto, M., Hirayama, T., Okaniwa, M., et al. (2015) · Nature Communications · doi:10.1038/ncomms8668 · Cited by 199
Coupling of Homologous Recombination and the Checkpoint by ATR
Buisson, R., Joshi, N., Rodrigue, A., Ho, C. K., Kreuzer, J., Foo, T. K., Hardy, É. J.-L., Dellaire, G., Haas, W., Xia, B., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2016.12.007 · Cited by 186
“U2OS and HeLa cells were treated with three different ATR inhibitors (ATRi, VE-821; ATRi#2, AZ20; ATRi#3, EPT46464) (Foote et al., 2013; Reaper et al., 2011; Toledo et al., 2011) and irradiated with IR, and RAD51 foci were analyzed in 2–4 hr (Figures 1A, 1B, S1A, and S1B).”
Method
Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR
Schoppy, D. W., Ragland, R. L., Gilad, O., Shastri, N., Peters, A. A., Murga, M., Fernández-Capetillo, Ó., Diehl, J. A., & Brown, E. J. (2011) · Journal of Clinical Investigation · doi:10.1172/jci58928 · Cited by 182
Replication Stress Drives Constitutive Activation of the DNA Damage Response and Radioresistance in Glioblastoma Stem-like Cells
Carruthers, R., Ahmed, S. U., Ramachandran, S., Strathdee, K. E., Kurian, K. M., Hedley, A., Gomez-Roman, N., Kalna, G., Neilson, M., Gilmour, L., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-0569 · Cited by 188
“15 of ATR (45), to target key elements of the DDR and RS responses.”
Background
Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells
Lloyd, R. L., Wijnhoven, P. W. G., Ramos‐Montoya, A., Wilson, Z., Illuzzi, G., Falenta, K., Jones, G. N., James, N. H., Chabbert, C. D., Stott, J., et al. (2020) · Oncogene · doi:10.1038/s41388-020-1328-y · Cited by 185
The DNA Damaging Revolution: PARP Inhibitors and Beyond
Yap, T. A., Plummer, R., Azad, N. S., & Helleday, T. (2019) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_238473 · Cited by 178
Targeting ATR and Chk1 kinases for cancer treatment: A new model for new (and old) drugs
Toledo, L. I., Murga, M., & Fernández-Capetillo, Ó. (2011) · Molecular Oncology · doi:10.1016/j.molonc.2011.07.002 · Cited by 180
“A similar toxicity for p53-deficient cells was also reported with an independent ATR inhibitor (Reaper et al., 2011).”
Background
Functions, Regulation, and Therapeutic Implications of the ATR Checkpoint Pathway
Yazinski, S. A., & Zou, L. (2016) · Annual Review of Genetics · doi:10.1146/annurev-genet-121415-121658 · Cited by 178
ATR Inhibitors VE-821 and VX-970 Sensitize Cancer Cells to Topoisomerase I Inhibitors by Disabling DNA Replication Initiation and Fork Elongation Responses
Jossé, R., Martin, S. E., Guha, R., Ormanoglu, P., Pfister, T. D., Reaper, P. M., Barnes, C. S., Jones, J. L., Charlton, P., Pollard, J. R., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-3369 · Cited by 181
“DDR molecular biomarkers induced by VE-281 Because VE-281 directly targets ATR (13,15) upstream from Chk1, we determined autophosphorylation of ATR on threonine 1989, a DNA damage activation site (30,31), and Chk1 phosphorylation on serine 345, which is mediated by ATR.”
BackgroundMethodResultInfluential
Targeting ATR as Cancer Therapy: A new era for synthetic lethality and synergistic combinations?
Bradbury, A., Hall, S., Curtin, N. J., & Drew, Y. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107450 · Cited by 180
PARP inhibitors: enhancing efficacy through rational combinations
Bhamidipati, D., Haro-Silerio, J. I., Yap, T. A., & Ngoi, N. Y. L. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02326-7 · Cited by 183
“Promising preclinical data has led to the development of several ATR inhibitors that have undergone clinical investigation [100].”
Background
Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors
Thomas, A., Redon, C. E., Sciuto, L. C., Padiernos, E., Ji, J. J., Lee, M.-J., Yuno, A., Lee, S., Zhang, Y., Tran, L. T.-N., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2017.76.6915 · Cited by 175
G-Quadruplex DNA as a Molecular Target for Induced Synthetic Lethality in Cancer Cells
McLuckie, K. I. E., Antonio, M. D., Zecchini, H. I., Xian, J., Caldas, C., Krippendorff, B., Tannahill, D., Lowe, C., & Balasubramanian, S. (2013) · Journal of the American Chemical Society · doi:10.1021/ja404868t · Cited by 177
Targeting radiation-resistant hypoxic tumour cells through ATR inhibition
Pires, I. M., Olcina, M. M., Anbalagan, S., Pollard, J. R., Reaper, P. M., Charlton, P., McKenna, W. G., & Hammond, E. M. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.265 · Cited by 175
“However, the selective ATR inhibitor VE-821 (3-amino-6- (4-(methylsulfonyl) phenyl)-N-phenylpyrazine-2carboxamide) was recently described (Charrier et al, 2011; Reaper et al, 2011).”
Background
DNA damage response inhibitors: Mechanisms and potential applications in cancer therapy
Carrassa, L., & Damia, G. L. M. (2017) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2017.08.013 · Cited by 178
Targeting the S and G2 checkpoint to treat cancer
Chen, T., Stephens, P., Middleton, F. K., & Curtin, N. J. (2011) · Drug Discovery Today · doi:10.1016/j.drudis.2011.12.009 · Cited by 176
Phosphatidylinositol 3-Kinase (PI3K) and Phosphatidylinositol 3-Kinase-Related Kinase (PIKK) Inhibitors: Importance of the Morpholine Ring
Andrš, M., Korábečný, J., Jun, D., Hodný, Z., Bártek, J., & Kuča, K. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm501026z · Cited by 164
Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development
Dreyer, S. B., Chang, D. K.-F., Bailey, P. J., & Biankin, A. V. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2411 · Cited by 168
Spliceosome Mutations Induce R Loop-Associated Sensitivity to ATR Inhibition in Myelodysplastic Syndromes
Nguyen, H. D., Leong, W. Y., Li, W., Reddy, P. N. G., Sullivan, J. D., Walter, M. J., Zou, L., & Graubert, T. A. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-3970 · Cited by 169
ATR-Mediated Phosphorylation of FANCI Regulates Dormant Origin Firing in Response to Replication Stress
Chen, Y.-H., Jones, M. V., Yin, Y., Crist, S. B., Colnaghi, L., Sims, R. J., Rothenberg, E., Jallepalli, P. V., & Huang, T. T. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.02.031 · Cited by 167
“Extracts with the indicated antibodies. ere subjected to coIP with anti-FANCI antibody or IgG control and analyzed by itor (VE-821) at 10 mM for 4 hr as indicated and analyzed by western blot. d dose of HU for 18 hr and were analyzed by western blot.”
Influential
ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor Activity as a Monotherapy and in Combination with Chemotherapy and the PARP Inhibitor Olaparib
Wilson, Z., Odedra, R., Wallez, Y., Wijnhoven, P. W. G., Hughes, A. M., Gerrard, J., Jones, G. N., Bargh-Dawson, H., Brown, E., Young, L. A., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-21-2997 · Cited by 166
“Reassuringly, the links between ATM, ARID1A, SETD2 and CCNE1 with ATRi sensitivity and/or replication stress have been previously described (3,8-11,18,43-45), although we did not observe any association with BRCA1/2 mutations.”
Background
Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations
Marshall, C. H., Sokolova, A. O., McNatty, A. L., Cheng, H. H., Eisenberger, M. A., Bryce, A. H., Schweizer, M. T., & Antonarakis, E. S. (2019) · European Urology · doi:10.1016/j.eururo.2019.02.002 · Cited by 162
Targeting the replication stress response in cancer
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Ataxia telangiectasia and Rad3-related inhibitors and cancer therapy: where we stand
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AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells
Min, A., Im, S., Jang, H., Kim, S., Lee, M., Kim, D. K., Yang, Y., Kim, H. J., Lee, K.-H., Kim, J. W., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0378 · Cited by 160
“Although a previous study indicated that an ATR inhibitor had a synergistic antitumor effect on ATM- or p53-deficient cancer cells when administered in combination with cisplatin in colorectal and lung cancer cell lines (14), the antitumor activity and underlying mechanisms of ATR inhibitor monotherapy on ATM status r…”
Background
Trial Watch: Targeting ATM–CHK2 and ATR–CHK1 pathways for anticancer therapy
Manic, G., Obrist, F., Sistigu, A., & Vitale, I. (2015) · Molecular & Cellular Oncology · doi:10.1080/23723556.2015.1012976 · Cited by 151
Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities
Sanjiv, K., Hagenkort, A., Calderón‐Montaño, J. M., Koolmeister, T., Reaper, P. M., Mortusewicz, O., Jacques, S. A., Kuiper, R., Schultz, N., Scobie, M., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.12.032 · Cited by 147
Biomarkers of Response and Resistance to DNA Repair Targeted Therapies
Stover, E. H., Konstantinopoulos, P. A., Matulonis, U. A., & Swisher, E. M. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0247 · Cited by 149
“Alterations causing increased replication stress may enhance sensitivity to ATM/ATR inhibition, for example, TP53 mutations, CCNE1 (Cyclin E1) amplifications (69, 70), and mutations in oncogenic drivers such as RAS and MYC (71, 72).”
Background
Linking hypoxia, DNA damage and proliferation in multicellular tumor spheroids
Riffle, S., Pandey, R. N., Albert, M., & Hegde, R. S. (2017) · BMC Cancer · doi:10.1186/s12885-017-3319-0 · Cited by 142
“(G2/M) after irradiation and hypoxia [22, 39], thus reducing cell survival.”
ATR Pathway Inhibition Is Synthetically Lethal in Cancer Cells with ERCC1 Deficiency
Mohni, K. N., Kavanaugh, G. M., & Cortez, D. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-3229 · Cited by 143
“ATR inhibitors also exhibit synthetic lethal interactions with ATM and XRCC1 deficiency as well as with cyclin E overexpression (15, 17, 19).”
BackgroundMethodInfluential
Drug discovery in advanced prostate cancer: translating biology into therapy
Yap, T. A., Smith, A. D., Ferraldeschi, R., Al‐Lazikani, B., Workman, P., & Bono, J. S. D. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.120 · Cited by 143
Targeting DNA damage repair in small cell lung cancer and the biomarker landscape
Sen, T., Gay, C. M., & Byers, L. A. (2018) · Translational Lung Cancer Research · doi:10.21037/tlcr.2018.02.03 · Cited by 138
“Preclinical observations suggest that ATR inhibitors may be especially active in TP53 and/or ATM deficient models from other tumor types (79).”
Background
Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies
Minchom, A. R., Aversa, C., & Lopez, J. S. (2018) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758835918786658 · Cited by 138
Genome-wide CRISPR screens reveal synthetic lethality of RNASEH2 deficiency and ATR inhibition
Wang, C., Wang, G., Feng, X., Shepherd, P. D. A., Zhang, J., Tang, M., Chen, Z., Srivastava, M., McLaughlin, M. E., Navone, N. M., et al. (2018) · Oncogene · doi:10.1038/s41388-018-0606-4 · Cited by 137
Two Distinct Modes of ATR Activation Orchestrated by Rad17 and Nbs1
Shiotani, B., Nguyen, H. D., Håkansson, P., Maréchal, A., Tse, A., Tahara, H., & Zou, L. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.04.018 · Cited by 142
“Using VE-821, a specific ATR inhibitor (Reaper et al., 2011), we confirmed that a number of ATR substrates, including Chk1, Rad17, RPA32, and ATR itself, were phosphorylated in an ATR-dependent manner after CPT treatment (Fig.”
Background
Inhibiting Wee1 and ATR kinases produces tumor-selective synthetic lethality and suppresses metastasis
Bukhari, A. B., Lewis, C. W., Pearce, J. J., Luong, D., Chan, G. K. T., & Gamper, A. M. (2019) · Journal of Clinical Investigation · doi:10.1172/jci122622 · Cited by 141
“Several studies have shown that in the absence of exogenous genotoxic stress 2 ATR inhibitors are well tolerated (28, 29) and cells from Seckel syndrome patients, who have 3”
Background
Human papillomavirus E6 and E7: What remains?
Vats, A., Trejo-Cerro, Ó., Thomas, M., & Banks, L. (2021) · Tumour Virus Research · doi:10.1016/j.tvr.2021.200213 · Cited by 141
“control after the loss of p53 [180,181], and it is possible this might apply to cells with abrogated p53 due to HPV infection.”
Background
CDK4/6 inhibitors induce replication stress to cause long‐term cell cycle withdrawal
Crozier, L., Foy, R., Mouery, B. L., Whitaker, R. H., Corno, A., Spanos, C., Ly, T., Cook, J. G., & Saurin, A. T. (2022) · The EMBO Journal · doi:10.15252/embj.2021108599 · Cited by 146
“This probably explains why 1 day of palbocicilib treatment is tolerable in RPE1 cells, despite a reduction in licenced origins, and why this is no longer tolerable when replication stress is elevated pharmacologically (Figs 4F and 5F and G).”
Replication stress and cancer: It takes two to tango
Lecona, E., & Fernández-Capetillo, Ó. (2014) · Experimental Cell Research · doi:10.1016/j.yexcr.2014.09.019 · Cited by 134
“Additionally, ATR inhibition was toxic for ATM deficient cells [87], a synthetic lethal effect that had already been described with mouse models [9].”
Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions
Basourakos, S. P., Li, L., Aparicio, A. M., Corn, P. G., Kim, J., & Thompson, T. C. (2016) · Current Medicinal Chemistry · doi:10.2174/0929867323666161214114948 · Cited by 136
Targeting DNA repair pathway in cancer: Mechanisms and clinical application
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Progress towards a clinically-successful ATR inhibitor for cancer therapy
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APOBEC3A and APOBEC3B Activities Render Cancer Cells Susceptible to ATR Inhibition
Buisson, R., Lawrence, M. S., Benes, C. H., & Zou, L. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-3389 · Cited by 129
Exploiting DNA repair defects in colorectal cancer
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“Several studies have identified a synthetic lethality with ATRi and ATM or p53 deficiency (Reaper et al., 2011; Toledo et al., 2011), and this effect is further increased when cells are also treated with genotoxic agents (Reaper et al., 2011; Shi et al., 2018).”
Background
Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours
Middleton, M. R., Dean, E. J., Evans, T. R. J., Shapiro, G. I., Pollard, J. R., Hendriks, B. S., Falk, M., Díaz-Padilla, I., & Plummer, R. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01405-x · Cited by 132
MRN, CtIP, and BRCA1 mediate repair of topoisomerase II–DNA adducts
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“Although the ATR inhibitor VE-821 (Reaper et al., 2011) had limited effect, the ATM inhibitor KU55933 (Hickson et al., 2004) rescued DNA replication to nearly 50% of the level observed in the absence of etoposide (Fig.”
ATM, ATR, CHK1, CHK2 and WEE1 inhibitors in cancer and cancer stem cells
Ronco, C., Martin, A. R., Demange, L., & Benhida, R. (2016) · MedChemComm · doi:10.1039/c6md00439c · Cited by 130
Topoisomerase degradation, DSB repair, p53 and IAPs in cancer cell resistance to camptothecin-like topoisomerase I inhibitors
Tomicic, M. T., & Kaina, B. (2012) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2012.09.002 · Cited by 123
Discovery of ATR kinase inhibitor berzosertib (VX-970, M6620): Clinical candidate for cancer therapy
Górecki, L., Andrš, M., Řezáčová, M., & Korábečný, J. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107518 · Cited by 123

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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