Targeting ATR in Cancer Medicine.
AT-rich interactive domain-containing protein 1A (ARID1A) deficiency
ATR inhibitors
Ataxia telangiectasia and Rad3-related protein (ATR)
Ataxia telangiectasia-mutated (ATM) deficiency
DNA damage response (DDR)
PARP inhibitors
Journal
Cancer treatment and research
ISSN: 0927-3042
Titre abrégé: Cancer Treat Res
Pays: United States
ID NLM: 8008541
Informations de publication
Date de publication:
2023
2023
Historique:
medline:
27
11
2023
pubmed:
18
11
2023
entrez:
17
11
2023
Statut:
ppublish
Résumé
As a key component of the DNA Damage Response, the Ataxia telangiectasia and Rad3-related (ATR) protein is a promising druggable target that is currently widely evaluated in phase I-II-III clinical trials as monotherapy and in combinations with other rational antitumor agents, including immunotherapy, DNA repair inhibitors, chemo- and radiotherapy. Ongoing clinical studies for this drug class must address the optimization of the therapeutic window to limit overlapping toxicities and refine the target population that will most likely benefit from ATR inhibition. With advances in the development of personalized treatment strategies for patients with advanced solid tumors, many ongoing ATR inhibitor trials have been recruiting patients based on their germline and somatic molecular alterations, rather than relying solely on specific tumor subtypes. Although a spectrum of molecular alterations have already been identified as potential predictive biomarkers of response that may sensitize to ATR inhibition, these biomarkers must be analytically validated and feasible to measure robustly to allow for successful integration into the clinic. While several ATR inhibitors in development are poised to address a clinically unmet need, no ATR inhibitor has yet received FDA-approval. This chapter details the underlying rationale for targeting ATR and summarizes the current preclinical and clinical landscape of ATR inhibitors currently in evaluation, as their regulatory approval potentially lies close in sight.
Identifiants
pubmed: 37978140
doi: 10.1007/978-3-031-30065-3_14
doi:
Substances chimiques
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Antineoplastic Agents
0
Biomarkers
0
ATR protein, human
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
239-283Informations de copyright
© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.
Références
Ngoi NYL, Peng G, Yap TA (2021) A Tale of Two Checkpoints: ATR Inhibition and PD-(L)1 Blockade. Annu Rev Med 73(1):1–20
Helleday T (2018) Targeting the DNA damage response for anti-cancer therapy. Canc Drug Disc Dev 1–9
Alhmoud JF, Woolley JF, Moustafa A-EA, Malki MI (2020) DNA damage/repair management in cancers. Cancers 12(4):1050
pubmed: 32340362
pmcid: 7226105
doi: 10.3390/cancers12041050
Mazouzi A, Velimezi G, Loizou JI (2014) DNA replication stress: causes, resolution and disease. Exp Cell Res 329(1):85–93
pubmed: 25281304
doi: 10.1016/j.yexcr.2014.09.030
Luo J, Solimini NL, Elledge SJ (2009) Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 138(4):807
doi: 10.1016/j.cell.2009.08.006
Bartkova J, Hořejší Z, Koed K, Krämer A, Tort F, Zieger K et al (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434(7035):864–870
pubmed: 15829956
doi: 10.1038/nature03482
Gorgoulis VG, Vassiliou L-VF, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T et al (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434(7035):907–913
Sundar R, Brown J, Russo AI, Yap TA (2017) Targeting ATR in cancer medicine. Curr Prob Cancer 41(4):302–315
doi: 10.1016/j.currproblcancer.2017.05.002
Branzei D, Foiani M (2010) Maintaining genome stability at the replication fork. Nat Rev Mol Cell Bio 11(3):208–219
doi: 10.1038/nrm2852
Ngoi NYL, Pham MM, Tan DSP, Yap TA (2021) Targeting the replication stress response through synthetic lethal strategies in cancer medicine. Trends Cancer 7(10):930–957
pubmed: 34215565
pmcid: 8458263
doi: 10.1016/j.trecan.2021.06.002
Berti M, Vindigni A (2016) Replication stress: getting back on track. Nat Struct Mol Biol 23(2):103–109
pubmed: 26840898
pmcid: 5125612
doi: 10.1038/nsmb.3163
Bradbury A, Hall S, Curtin N, Drew Y (2020) Targeting ATR as Cancer Therapy: A new era for synthetic lethality and synergistic combinations? Pharmacol Therapeut. 207:107450
doi: 10.1016/j.pharmthera.2019.107450
Baillie KE, Stirling PC (2020) Beyond kinases: targeting replication stress proteins in cancer therapy. Trends Cancer 7(5):430–446
pubmed: 33203609
doi: 10.1016/j.trecan.2020.10.010
Lecona E, Fernandez-Capetillo O (2018) Targeting ATR in cancer. Nat Rev Cancer 18(9):586–595
pubmed: 29899559
doi: 10.1038/s41568-018-0034-3
Wang X, Wang L, Huang Y, Deng Z, Li C, Zhang J et al (2022) A plant-specific module for homologous recombination repair. Proc Natl Acad Sci 119(16):e2202970119
pubmed: 35412914
pmcid: 9169791
doi: 10.1073/pnas.2202970119
Rundle S, Bradbury A, Drew Y, Curtin NJ (2017) Targeting the ATR-CHK1 axis in cancer therapy. Cancers 9(5):41
pubmed: 28448462
pmcid: 5447951
doi: 10.3390/cancers9050041
Bass TE, Cortez D (2019) Quantitative phosphoproteomics reveals mitotic function of the ATR activator ETAA1. J Cell Biol 218(4):1235–1249
pubmed: 30755469
pmcid: 6446857
doi: 10.1083/jcb.201810058
Zou L, Elledge SJ (2003) Sensing DNA damage through ATRIP Recognition of RPA-ssDNA complexes. Science 300(5625):1542–1548
pubmed: 12791985
doi: 10.1126/science.1083430
Butler LR, Gilad O, Brown EJ (2018) Targeting the DNA damage response for anti-cancer therapy. Canc Drug Disc Dev 11–33
Couch FB, Bansbach CE, Driscoll R, Luzwick JW, Glick GG, Bétous R et al (2013) ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Gene Dev 27(14):1610–1623
pubmed: 23873943
pmcid: 3731549
doi: 10.1101/gad.214080.113
Matos DA, Zhang J-M, Ouyang J, Nguyen HD, Genois M-M, Zou L (2020) ATR protects the genome against R loops through a MUS81-triggered feedback loop. Mol Cell 77(3):514-527.e4
pubmed: 31708417
doi: 10.1016/j.molcel.2019.10.010
Sørensen CS, Hansen LT, Dziegielewski J, Syljuåsen RG, Lundin C, Bartek J et al (2005) The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nat Cell Biol 7(2):195–201
pubmed: 15665856
doi: 10.1038/ncb1212
Wang LC, Gautier J (2010) The Fanconi anemia pathway and ICL repair: implications for cancer therapy. Crit Rev Biochem Mol 45(5):424–439
doi: 10.3109/10409238.2010.502166
Sirbu BM, Cortez D (2013) DNA damage response: three levels of DNA repair regulation. Csh Perspect Biol 5(8):a012724
Auclair Y, Rouget R, Drobetsky EA (2009) ATR kinase as master regulator of nucleotide excision repair during S phase of the cell cycle. Cell Cycle 8(12):1865–1871
pubmed: 19440044
doi: 10.4161/cc.8.12.8800
Lee T-H, Park J-M, Leem S-H, Kang T-H (2014) Coordinated regulation of XPA stability by ATR and HERC2 during nucleotide excision repair. Oncogene 33(1):19–25
pubmed: 23178497
doi: 10.1038/onc.2012.539
Fokas E, Prevo R, Hammond EM, Brunner TB, McKenna WG, Muschel RJ (2014) Targeting ATR in DNA damage response and cancer therapeutics. Cancer Treat Rev 40(1):109–117
pubmed: 23583268
doi: 10.1016/j.ctrv.2013.03.002
Kim D, Liu Y, Oberly S, Freire R, Smolka MB (2018) ATR-mediated proteome remodeling is a major determinant of homologous recombination capacity in cancer cells. Nucleic Acids Res 46(16):8311–8325
pubmed: 30010936
pmcid: 6144784
doi: 10.1093/nar/gky625
Kantidze OL, Velichko AK, Luzhin AV, Petrova NV, Razin SV (2018) Synthetically lethal interactions of atm, ATR, and DNA-PKcs. Trends Cancer 4(11):755–768
pubmed: 30352678
doi: 10.1016/j.trecan.2018.09.007
Qiu Z, Oleinick NL, Zhang J (2018) ATR/CHK1 inhibitors and cancer therapy. Radiother Oncol 126(3):450–464
pubmed: 29054375
doi: 10.1016/j.radonc.2017.09.043
Weber AM, Ryan AJ (2015) ATM and ATR as therapeutic targets in cancer. Pharmacol Therapeut. 149:124–138
doi: 10.1016/j.pharmthera.2014.12.001
Hurley PJ, Wilsker D, Bunz F (2007) Human cancer cells require ATR for cell cycle progression following exposure to ionizing radiation. Oncogene 26(18):2535–2542
pubmed: 17043640
doi: 10.1038/sj.onc.1210049
Mei L, Zhang J, He K, Zhang J (2019) Ataxia telangiectasia and Rad3-related inhibitors and cancer therapy: where we stand. J Hematol Oncol 12(1):43
pubmed: 31018854
pmcid: 6482552
doi: 10.1186/s13045-019-0733-6
Nishida H, Tatewaki N, Nakajima Y, Magara T, Ko KM, Hamamori Y et al (2009) Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response. Nucleic Acids Res 37:5678–5689. Available from <Go to ISI>://WOS:000271569100009
Toledo LI, Murga M, Zur R, Soria R, Rodriguez A, Martinez S et al (2011) A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol 18(6):721–U124. Available from <Go to ISI>://WOS:000291308000014
Charrier JD, Durrant SJ, Golec JMC, Kay DP, Knegtel RMA, MacCormick S et al (2011) Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J Med Chem 54:2320–2330. Available from <Go to ISI>://WOS:000289215700028
Reaper PM, Griffiths MR, Long JM, Charrier JD, MacCormick S, Charlton PA et al (2011) Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol 7:428–430. Available from <Go to ISI>://WOS:000292252100008
Huntoon CJ, Flatten KS, Hendrickson AEW, Huehls AM, Sutor SL, Kaufmann SH et al (2013) ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status. Cancer Res 73:3683–3691. Available from <Go to ISI>://WOS:000320380300020
Kastan MB, Zhan QM, Eldeiry WS, Carrier F, Jacks T, Walsh WV et al (1992) A mammalian-cell cycle checkpoint pathway utilizing P53 and Gadd45 Is defective in ataxia-telangiectasia. Cell 71:587–597. Available from <Go to ISI>://WOS:A1992JY67600007
Wengner AM, Siemeister G, Lucking U, Lefranc J, Wortmann L, Lienau P et al (2020) The novel ATR inhibitor BAY 1895344 is efficacious as monotherapy and combined with DNA damage-inducing or repair-compromising therapies in preclinical cancer models. Mol Cancer Ther 19(1):26–38. Available from <Go to ISI>://WOS:000505667900003
Knegtel R, Charrier JD, Durrant S, Davis C, O’Donnell M, Storck P et al (2019) Rational design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970,M6620): optimization of intra- and intermolecular polar interactions of a new ataxia telangiectasia mutated and Rad3-related (ATR) kinase inhibitor. J Med Chem 62:5547–5561. Available from <Go to ISI>://WOS:000471834500020
Hall AB, Newsome D, Wang Y, Boucher DM, Eustace B, Gu Y et al (2014) Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970. Oncotarget 5(14):5674–5685
pubmed: 25010037
pmcid: 4170644
doi: 10.18632/oncotarget.2158
Nagel R, Avelar AT, Aben N, Proost N, Ven M van de, van der Vliet J et al (2019) Inhibition of the replication stress response is a synthetic vulnerability in SCLC that acts synergistically in combination with cisplatin. Mol Cancer Ther 18:762–770. Available from <Go to ISI>://WOS:000462996800004
Kurmasheva RT, Kurmashev D, Reynolds CP, Kang M, Wu J, Houghton PJ et al (2018) 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. Pediatr Blood Cancer 65(2):e26825
doi: 10.1002/pbc.26825
Leszczynska KB, Dobrynin G, Leslie RE, Ient J, Boumelha AJ, Senra JM et al (2016) Preclinical testing of an Atr inhibitor demonstrates improved response to standard therapies for esophageal cancer. Radiother Oncol 121(2):232–238
pubmed: 27839769
pmcid: 5154234
doi: 10.1016/j.radonc.2016.10.023
Combes E, Andrade AF, Tosi D, Michaud HA, Coquel F, Garambois V et al (2019) Inhibition of Ataxia-telangiectasia mutated and RAD3-related (ATR) overcomes oxaliplatin resistance and promotes antitumor immunity in colorectal cancer. Cancer Res 79:2933–2946. Available from <Go to ISI>://WOS:000470291600015
Tu XY, Kahila MM, Zhou Q, Yu J, Kalari KR, Wang LW et al (2018) ATR inhibition is a promising radiosensitizing strategy for triple-negative breast cancer. Mol Cancer Ther 17:2462–2472. Available from <Go to ISI>://WOS:000448888000017
Middleton MR, Dean E, Evans TRJ, Shapiro GI, Pollard J, Hendriks BS et al (2021) Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine +/− cisplatin in patients with advanced solid tumours. Brit J Cancer 125(4):510–59. Available from <Go to ISI>://WOS:000655068600003
Yazinski SA, Comaills V, Buisson R, Genois MM, Nguyen HD, Ho CK et al (2017) ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Gene Dev 31(3):318–332. Available from <Go to ISI>://WOS:00039579610001
Yap TA, O’Carrigan B, Penney MS, Lim JS, Brown JS, Luken MJD et al (2020) 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. J Clin Oncol 38(27):3195–+. Available from <Go to ISI>://WOS:000574579100010
Konstantinopoulos PA, Cheng SC, Hendrickson AEW, Penson RT, Schumer ST, Doyle LA et al (2020) Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial. Lancet Oncology 21:957–9568. Available from <Go to ISI>://WOS:000545328900033
Konstantinopoulos PA, da Costa AABA, Gulhan D, Lee EK, Cheng S-C, Hendrickson AEW et al (2021) A replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer. Nat Commun 12(1):5574
pubmed: 34552099
pmcid: 8458434
doi: 10.1038/s41467-021-25904-w
Shapiro GI, Wesolowski R, Devoe C, Lord S, Pollard J, Hendriks BS et al (2021) Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours. Brit J Cancer 125:520–57. Available from <Go to ISI>://WOS:000655068600001
Thomas A, Redon CE, Sciuto L, Padiernos E, Ji JP, Lee MJ et al (2018) Phase I study of ATR Inhibitor M6620 in combination with topotecan in patients with advanced solid tumors. J Clin Oncol 2018;36:1594–+. Available from <Go to ISI>://WOS:000434262900008
Thomas A, Takahashi N, Rajapakse VN, Zhang XH, Sun YL, Ceribelli M et al (2021) Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress. Cancer Cell 39:566–+. Available from <Go to ISI>://WOS:000640027300015
Merck_KGaA (2022). Merck KGaA, Darmstadt, Germany, advances development programs in oncology focusing on novel mechanisms and pathways. Cited 27 Dec 2022. Available from https://www.emdgroup.com/en/news/development-projects-in-oncology-03-06-2022.html
Foote KM, Nissink JWM, McGuire T, Turner P, Guichard S, Yates JWT et al (2018) Discovery and Characterization<Go to ISI>://WOS:000451496300005 of AZD6738, a potent inhibitor of ataxia telangiectasia mutated and Rad3 related (ATR) kinase with application as an anticancer agent. J Med Chem 61:9889–9907. Available from
Jones CD, Blades K, Foote KM, Guichard SM, Jewsbury PJ, McGuire T et al (2013) Abstract 2348: Discovery of AZD6738, a potent and selective inhibitor with the potential to test the clinical efficacy of ATR kinase inhibition in cancer patients. Cancer Res 73(8_Supplement):2348–2348
Kwok M, Davies N, Agathanggelou A, Smith E, Oldreive C, Petermann E et al (2016) ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells. Blood 127(5):582–595
pubmed: 26563132
doi: 10.1182/blood-2015-05-644872
Wilson Z, Odedra R, Wallez Y, Wijnhoven PWG, Hughes AM, Gerrard J et al (2022) ATR inhibitor AZD6738 (ceralasertib) exerts antitumor activity as a monotherapy and in combination with chemotherapy and the PARP inhibitor olaparib. Cancer Res 82:1140–1152. Available from <Go to ISI>://WOS:000772155800001
Sundar R, Brown J, Russo AI, Yap TA (2017) Targeting ATR in cancer medicine. Curr Prob Cancer 41(4):302–315. Available from https://www.ncbi.nlm.nih.gov/pubmed/28662958
Dillon M, Guevara J, Mohammed K, Smith SA, Dean E, McLellan L et al (2019) A phase I study of ATR inhibitor, AZD6738, as monotherapy in advanced solid tumours (PATRIOT part A, B). Ann Oncol 30:165–+. Available from <Go to ISI>://WOS:000491295501267
Guichard SM, Brown E, Odedra R, Hughes A, Heathcote D, Barnes J et al (2013) The pre-clinical in vitro and in vivo activity of AZD6738: A potent and selective inhibitor of ATR kinase. Cancer Res 73. Available from <Go to ISI>://WOS:000331220602050
Vendetti FP, Lau A, Schamus S, Conrads TP, O’Connor MJ, Bakkenist CJ (2015) The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. Oncotarget 6(42):44289–44305
pubmed: 26517239
pmcid: 4792557
doi: 10.18632/oncotarget.6247
Kim H, Min A, Im S, Jang H, Lee KH, Lau A et al (2017) Anti-tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells. Int J Cancer 140(1):109–119
pubmed: 27501113
doi: 10.1002/ijc.30373
Yap TA, Krebs MG, Postel-Vinay S, El-Khouiery A, Soria JC, Lopez J et al (2021) Ceralasertib (AZD6738), an oral ATR kinase inhibitor, in combination with carboplatin in patients with advanced solid tumors: a phase I study. Clin Cancer Res 27:5213–5224. Available from: https://www.ncbi.nlm.nih.gov/pubmed/34301752
Kim ST, Smith SA, Mortimer P, Loembe AB, Cho H, Kim KM et al (2021) Phase I study of ceralasertib (AZD6738), a novel DNA damage repair agent, in combination with weekly paclitaxel in refractory cancer. Clin Cancer Res 27:4700–4709. Available from: https://www.ncbi.nlm.nih.gov/pubmed/33975862
Paula BH de, Basu B, Mander A, Khan J, Bundi P, Goodwin R et al (2021) ATRiUM: a first-in-human dose escalation phase I trial of ceralasertib (AZD6738) and gemcitabine as combination therapy. Cancer Res 81. Available from <Go to ISI>://WOS:000680263501296
Dunlop CR, Wallez Y, Johnson TI, Fernandez SBD, Durant ST, Cadogan EB et al (2020) Complete loss of ATM function augments replication catastrophe induced by ATR inhibition and gemcitabine in pancreatic cancer models. Brit J Cancer. 123:1424–1436. Available from Available from: <Go to ISI>://WOS:000554842400004
Bukhari AB, Lewis CW, Pearce JJ, Luong D, Chan GK, Gamper AM (2019) Inhibiting Wee1 and ATR kinases produces tumor-selective synthetic lethality and suppresses metastasis. J Clin Investig 129:1329–1344. Available from <Go to ISI>://WOS:000460125800037
Jin J, Fang HH, Yang F, Ji WF, Guan N, Sun ZJ et al (2018) Combined Inhibition of ATR and WEE1 as a novel therapeutic strategy in triple-negative breast cancer. Neoplasia 20:478–488. Available from <Go to ISI>://WOS:000430688400007
Krebs MG, Lopez J, El-Khoueiry A, Bang YJ, Postel-Vinay S, Abida W et al (2018) Phase I study of AZD6738, an inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or durvalumab in patients (pts) with advanced solid cancers. Cancer Res 78(13_Supplement):CT026–CT026. Available from <Go to ISI>://WOS:000468818900025
Aggarwal R, Umetsu S, Dhawan M, Grabowsky J, Carnevale J, Howell M et al (2021) Interim results from a phase II study of the ATR inhibitor ceralasertib in ARID1A-deficient and ARID1A-intact advanced solid tumor malignancies. Ann Oncol 32:S583–S583. Available from <Go to ISI>://WOS:000700527700488
Shah PD, Wethington SL, Pagan C, Latif N, Tanyi J, Martin LP et al (2021) Combination ATR and PARP Inhibitor (CAPRI): a phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer. Gynecol Oncol. 163(2):246–253. Available from <Go to ISI>://WOS:000714728500005
Besse B, Awad M, Forde P, Thomas M, Park K, Goss G et al (2021) HUDSON: an open-label, multi-drug, biomarker-directed, phase II platform study in patients with NSCLC, who progressed on anti-PD(L)1 therapy. J Thorac Oncol 16:S118–S119. Available from <Go to ISI>://WOS:000631349600099
Kwon M, Kim G, Kim R, Kim KT, Kim ST, Smith S et al (2022) Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced gastric cancer. J Immunother Cancer 10. Available from <Go to ISI>://WOS:000821480200001
Hernandez M, Besse B, Awad M, Forde P, Thomas M, Park K et al (2021) Immuno-modulatory effects of ceralasertib in combination with durvalumab in NSCLC with progression on anti-PD(L)1 treatment (HUDSON). J Thorac Oncol 16:S350–S350. Available from <Go to ISI>://WOS:000631349600531
Lucking U, Wortmann L, Wengner AM, Lefranc J, Lienau P, Briem H et al (2020) Damage incorporated: discovery of the potent, highly selective, orally available ATR inhibitor BAY 1895344 with favorable pharmacokinetic properties and promising efficacy in monotherapy and in combination treatments in preclinical tumor models. J Med Chem 63:7293–7325. Available from <Go to ISI>://WOS:000550753700043
Szydzik J, Lind DE, Arefin B, Kurhe Y, Umapathy G, Siaw JT et al (2021) ATR inhibition enables complete tumour regression in ALK-driven NB mouse models. Nat Commun 12. Available from <Go to ISI>://WOS:000722322900021
Yap TA, Tan DSP, Terbuch A, Caldwell R, Guo C, Goh BC et al (2021) First-in-human trial of the oral ataxia telangiectasia and RAD3-related (ATR) inhibitor BAY 1895344 in patients with advanced solid tumors. Cancer Discov 11(1):80–91. Available from <Go to ISI>://WOS:000607017700021
Austin WR, Armijo AL, Campbell DO, Singh AS, Hsieh T, Nathanson D et al (2012) Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress. J Exp Med 209:2215–2228. Available from <Go to ISI>://WOS:000311295600008
Jo U, Murai Y, Takebe N, Thomas A, Pommier Y (2021) Precision Oncology with drugs targeting the replication stress, ATR, and schlafen 11. Cancers 13(18):4601
pubmed: 34572827
pmcid: 8465591
doi: 10.3390/cancers13184601
Jo U, Senatorov IS, Zimmermann A, Saha LK, Murai Y, Kim SH et al (2021) Novel and highly potent ATR inhibitor M4344 kills cancer cells with replication stress, and enhances the chemotherapeutic activity of widely used DNA damaging agents. Mol Cancer Ther 20(8):1431–1441
pubmed: 34045232
pmcid: 9398135
doi: 10.1158/1535-7163.MCT-20-1026
Zenke FT, Zimmermann A, Dahmen H, Elenbaas B, Pollard J, Reaper P et al (2019) Abstract 369: Antitumor activity of M4344, a potent and selective ATR inhibitor, in monotherapy and combination therapy. Cancer Res 79(13_Supplement):369
Jo U, Senatorov IS, Zimmermann A, Saha LK, Murai Y, Kim SH et al (2021) Novel and highly potent ATR inhibitor M4344 kills cancer cells with replication stress, and enhances the chemotherapeutic activity of widely used DNA damaging agents. Mol Cancer Ther 20:1431–1441. Available from <Go to ISI>://WOS:000680862700011
Roulston A, Zimmermann M, Papp R, Skeldon A, Pellerin C, Dumas-Bérube É et al (2021) RP-3500: A novel, potent, and selective atr inhibitor that is effective in preclinical models as a monotherapy and in combination with PARP inhibitors. Mol Cancer Ther 21(2):245–256
pubmed: 34911817
pmcid: 9398170
doi: 10.1158/1535-7163.MCT-21-0615
Yap T, Lee E, Spigel D, Fontana E, Højgaard M, Lheureux S et al (2021) Abstract CC04-01: first-in-human biomarker-driven phase I TRESR trial of ataxia telangiectasia and Rad3-related inhibitor (ATRi) RP-3500 in patients (pts) with advanced solid tumors harboring synthetic lethal (SL) genomic alterations. Mol Cancer Ther 20(12_Supplement):CC04-01–CC04-01
Zhang Y, Hreiki J, Wilkinson G, Ploeger B. Alternative dosing schedules for therapeutic window optimization for the ataxia telangiectasia and Rad3-related pathway (Atr) inhibitor elimusertib in patients with advanced solid tumors: M&S-based exploration using phase 1 data. Clin Pharmacol Ther 111:S41–S41. Available from <Go to ISI>://WOS:000752207700140
Yap TA, Tolcher AW, Plummer ER, Becker A, Fleuranceau-Morel P, Goddemeier T et al (2021) A first-in-human phase I study of ATR inhibitor M1774 in patients with solid tumors. J Clin Oncol 39:TPS3153–TPS3153. Available from: https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.TPS3153
Patel M, Moore KN, Piscitello D, Majithiya J, Luzarraga MR, Millward H et al (2022) Abstract LB520: a pharmacodynamic platform using liquid biopsy to support dose selection for the ATR inhibitor ART0380 (IACS-030380). Cancer Res 82:LB520–LB520. Available from: https://doi.org/10.1158/1538-7445.AM2022-LB520
McCabe N, Lord CJ, Tutt AN, Martin N, Smith GCM, Ashworth A (2005) BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of poly (ADP-ribose) polymerase: an issue of potency. Cancer Biol Ther 4(9):934–936
pubmed: 16251802
doi: 10.4161/cbt.4.9.2141
McCabe N, Turner NC, Lord CJ, Kluzek K, Białkowska A, Swift S et al (2006) Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 66(16):8109–8115
pubmed: 16912188
doi: 10.1158/0008-5472.CAN-06-0140
Farmer H, McCabe N, Lord CJ, Tutt ANJ, Johnson DA, Richardson TB et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921
pubmed: 15829967
doi: 10.1038/nature03445
Sachdev E, Tabatabai R, Roy V, Rimel BJ, Mita MM (2019) PARP Inhibition in cancer: an update on clinical development. Target Oncol 14(6):657–679
pubmed: 31625002
doi: 10.1007/s11523-019-00680-2
Topatana W, Juengpanich S, Li S, Cao J, Hu J, Lee J et al (2020) Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation. J Hematol Oncol 13(1):118
pubmed: 32883316
pmcid: 7470446
doi: 10.1186/s13045-020-00956-5
Brown TJ, Reiss KA (2021) PARP inhibitors in pancreatic cancer. Cancer J 27(6):465–475
pubmed: 34904809
pmcid: 8682800
doi: 10.1097/PPO.0000000000000554
Tripathi A, Balakrishna P, Agarwal N (2020) PARP inhibitors in castration-resistant prostate cancer. Cancer Treat Res Commun. 24:100199
pubmed: 32745972
doi: 10.1016/j.ctarc.2020.100199
Li X, Heyer W-D (2008) Homologous recombination in DNA repair and DNA damage tolerance. Cell Res 18(1):99–113
pubmed: 18166982
doi: 10.1038/cr.2008.1
Haynes B, Murai J, Lee J-M (2018) Restored replication fork stabilization, a mechanism of PARP inhibitor resistance, can be overcome by cell cycle checkpoint inhibition. Cancer Treat Rev 71:1–7
pubmed: 30269007
pmcid: 7429716
doi: 10.1016/j.ctrv.2018.09.003
Turner NC, Lord CJ, Iorns E, Brough R, Swift S, Elliott R et al (2008) A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. Embo J 27(9):1368–1377
pubmed: 18388863
pmcid: 2374839
doi: 10.1038/emboj.2008.61
Sanjiv K, Hagenkort A, Calderón-Montaño JM, Koolmeister T, Reaper PM, Mortusewicz O et al (2016) Cancer-specific synthetic lethality between ATR and CHK1 kinase activities. Cell Rep 17(12):3407–3416
pubmed: 28009306
pmcid: 5638787
doi: 10.1016/j.celrep.2016.12.031
Toledo LI, Altmeyer M, Rask M-B, Lukas C, Larsen DH, Povlsen LK et al (2014) ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell 156(1–2):374
doi: 10.1016/j.cell.2014.01.001
Kim H, George E, Ragland RL, Rafail S, Zhang R, Krepler C et al (2017) Targeting the ATR/CHK1 axis with PARP inhibition results in tumor regression in BRCA-mutant ovarian cancer models. Clin Cancer Res 23(12):3097–3108
pubmed: 27993965
doi: 10.1158/1078-0432.CCR-16-2273
Krebs MG, Lopez J, El-Khoueiry A, Bang Y-J, Postel-Vinay S, Abida W et al (2018) Abstract CT026: Phase I study of AZD6738, an inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or durvalumab in patients (pts) with advanced solid cancers. Cancer Res 78(13_Supplement):CT026–CT026
Wethington SL, Shah PD, Martin LP, Tanyi JL, Latif NA, Morgan MA et al (2021) Combination of PARP and ATR inhibitors (olaparib and ceralasertib) shows clinical activity in acquired PARP inhibitor-resistant recurrent ovarian cancer. J Clin Oncol 39(15_suppl):5516–5516
Shah PD, Wethington SL, Pagan C, Latif N, Tanyi J, Martin LP et al (2021) Combination ATR and PARP Inhibitor (CAPRI): a phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer. Gynecol Oncol 163(2):246–253
pubmed: 34620496
pmcid: 9614917
doi: 10.1016/j.ygyno.2021.08.024
Schoonen PM, Kok YP, Wierenga E, Bakker B, Foijer F, Spierings DCJ et al (2019) Premature mitotic entry induced by ATR inhibition potentiates olaparib inhibition-mediated genomic instability, inflammatory signaling, and cytotoxicity in BRCA2-deficient cancer cells. Mol Oncol. 13:2422–2440. Available from <Go to ISI>://WOS:000491106400001
Parkes EE, Walker SM, Taggart LE, McCabe N, Knight LA, Wilkinson R et al (2017) Activation of STING-dependent innate immune signaling by S-phase-specific DNA damage in breast cancer. J Natl Cancer Inst 109. Available from https://www.ncbi.nlm.nih.gov/pubmed/27707838
Pilie P, Tang Z, Park S, Wu C, Dong ZY, Yap T et al (2019) Inhibitors of Ataxia-Telangiectasia Related (ATR) protein lead to innate immune pathway activation and enhanced response to immune therapy in prostate cancer. Journal for Immunotherapy of Cancer. 7. Available from <Go to ISI>://WOS:000496473200135
Sheng HL, Huang Y, Xiao YZ, Zhu ZR, Shen MY, Zhou PT et al (2020) ATR inhibitor AZD6738 enhances the antitumor activity of radiotherapy and immune checkpoint inhibitors by potentiating the tumor immune microenvironment in hepatocellular carcinoma. J Immunother Cancer 8. Available from <Go to ISI>://WOS:000553971800001
Dillon MT, Bergerhoff KF, Pedersen M, Whittock H, Crespo-Rodriguez E, Patin EC et al (2019) ATR inhibition potentiates the radiation-induced inflammatory tumor microenvironment. Clin Cancer Res 25:3392–3403. Available from <Go to ISI>://WOS:000470293000021
Gasser S, Orsulic S, Brown EJ, Raulet DH (2005) The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436:1186–1190. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15995699
Sato H, Niimi A, Yasuhara T, Permata TBM, Hagiwara Y, Isono M et al (2017) DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat Commun 8:1751. Available from https://www.ncbi.nlm.nih.gov/pubmed/29170499
Chen CF, Ruiz-Vega R, Vasudeva P, Espitia F, Krasieva TB, de Feraudy S et al (2017) ATR mutations promote the growth of melanoma tumors by modulating the immune microenvironment. Cell Rep 18:2331–2342. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28273450
Lee J, Kim ST, Smith S, Mortimer PG, Loembe B, Hong J et al (2020) Results from a phase I, open-label study of ceralasertib (AZD6738), a novel DNA damage repair agent, in combination with weekly paclitaxel in refractory cancer (NCT02630199). J Clin Oncol 38. Available from <Go to ISI>://WOS:000560368301399
Louie AD, Huntington K, Carlsen L, Zhou L, El-Deiry WS (2021) Integrating molecular biomarker inputs into development and use of clinical cancer therapeutics. Front Pharmacol 12:747194
pubmed: 34737704
pmcid: 8560682
doi: 10.3389/fphar.2021.747194
Ngoi NYL, Westin SN, Yap TA (2022) Targeting the DNA damage response beyond poly(ADP-ribose) polymerase inhibitors: novel agents and rational combinations. Curr Opin Oncol 34(5):559–569
pubmed: 35787597
pmcid: 9371461
doi: 10.1097/CCO.0000000000000867
Pilie PG, Gheeya JS, Kyewalabye K, Goswamy RV, Wani KM, Le H, et al. Identifying functional loss of ATM gene in patients with advanced cancer. J Clin Oncol 38(15_suppl):3629–3629
Rafiei S, Fitzpatrick K, Liu D, Cai M-Y, Elmarakeby HA, Park J et al (2020) ATM loss confers greater sensitivity to ATR inhibition than PARP inhibition in prostate cancer. Cancer Res 80(11):2094–2100
pubmed: 32127357
pmcid: 7272301
doi: 10.1158/0008-5472.CAN-19-3126
Yap TA, Tan DSP, Terbuch A, Caldwell R, Guo C, Goh BC et al (2021) First-in-human trial of the oral ataxia telangiectasia and RAD3-related (ATR) inhibitor BAY 1895344 in patients with advanced solid tumors. Cancer Discov 11(1):80–91
pubmed: 32988960
doi: 10.1158/2159-8290.CD-20-0868
Kwok M, Davies N, Agathanggelou A (2016) ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells (vol 127, p 582, 2016). Blood 127:2647–2647. Available from <Go to ISI>://WOS:000378334400022
Middleton FK, Pollard JR, Curtin NJ (2018) The impact of p53 dysfunction in ATR inhibitor cytotoxicity and chemo- and radiosensitisation. Cancers 10(8):275
pubmed: 30127241
pmcid: 6116113
doi: 10.3390/cancers10080275
Dillon MT, Barker HE, Pedersen M, Hafsi H, Bhide SA, Newbold KL et al (2017) Radiosensitization by the ATR inhibitor AZD6738 through generation of acentric micronuclei. Mol Cancer Ther 16(1):25–34
pubmed: 28062704
doi: 10.1158/1535-7163.MCT-16-0239
Das S, Whisenant J, Doyle A, Allegra CJ, Berlin J (2019) A phase II study of M6620 and irinotecan in TP53 mutant gastric and gastroesophageal junction (GEJ) adenocarcinoma patients (pts) [NCT03641313]. J Clin Oncol 37(4_suppl):TPS175–TPS175
Williamson CT, Miller R, Pemberton HN, Jones SE, Campbell J, Konde A et al (2016) ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. Nat Commun 7(1):13837
pubmed: 27958275
pmcid: 5159945
doi: 10.1038/ncomms13837
Tsai S, Fournier L-A, Chang EY, Wells JP, Minaker SW, Zhu YD et al (2021) ARID1A regulates R-loop associated DNA replication stress. Plos Genet 17(4):e1009238
pubmed: 33826602
pmcid: 8055027
doi: 10.1371/journal.pgen.1009238
Aggarwal R, Umetsu S, Dhawan M, Grabowsky J, Carnevale J, Howell M et al (2021) 512O Interim results from a phase II study of the ATR inhibitor ceralasertib in ARID1A-deficient and ARID1A-intact advanced solid tumor malignancies. Ann Oncol 32:S583
doi: 10.1016/j.annonc.2021.08.1034
Yap TA, O’Carrigan B, Penney MS, Lim JS, Brown JS, Luken MJ de M et al (2020) 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. J Clin Oncol 38(27):3195–3204
Krajewska M, Fehrmann RSN, Schoonen PM, Labib S, de Vries EGE, Franke L et al (2015) ATR inhibition preferentially targets homologous recombination-deficient tumor cells. Oncogene 34(26):3474–3481
pubmed: 25174396
doi: 10.1038/onc.2014.276
Toh M, Ngeow J (2021) Homologous recombination deficiency: cancer predispositions and treatment implications. Oncol 26(9):e1526–e1537
doi: 10.1002/onco.13829
Buisson R, Lawrence MS, Benes CH, Zou L (2017) APOBEC3A and APOBEC3B activities render cancer cells susceptible to ATR inhibition. Cancer Res 77(17):4567–4578
pubmed: 28698210
pmcid: 5609510
doi: 10.1158/0008-5472.CAN-16-3389
Savva C, Souza KD, Ali R, Rakha EA, Green AR, Madhusudan S (2019) Clinicopathological significance of ataxia telangiectasia-mutated (ATM) kinase and ataxia telangiectasia-mutated and Rad3-related (ATR) kinase in MYC overexpressed breast cancers. Breast Cancer Res Tr 175(1):105–115
doi: 10.1007/s10549-018-05113-8
Kok YP, Llobet SG, Schoonen PM, Everts M, Bhattacharya A, Fehrmann RSN et al (2020) Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors. Oncogenesis 9(10):88
pubmed: 33028815
pmcid: 7542455
doi: 10.1038/s41389-020-00270-2
Ngoi N, Lin HY, Dumbrava EE, Fu S, Karp DD, Naing A et al (2022) Baseline predictors of hematological toxicity in patients with advanced cancer treated with ATR inhibitors in phase I/II clinical trials. J Clin Oncol 40(16_suppl):3111–3111
Fernandez-Rozadilla C, Simões AR, Lleonart ME, Carnero A, Carracedo Á (2021) Tumor profiling at the service of cancer therapy. Frontiers Oncol 10:595613
doi: 10.3389/fonc.2020.595613
Fountzilas E, Tsimberidou AM, Vo HH, Kurzrock R (2022) Clinical trial design in the era of precision medicine. Genome Med 14(1):101
pubmed: 36045401
pmcid: 9428375
doi: 10.1186/s13073-022-01102-1