{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:17:35Z","timestamp":1791299855592,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T00:00:00Z","timestamp":1692576000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AstraZeneca"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Ataxia-telangiectasia mutated gene (ATM) is a key component of the DNA damage response (DDR) and double-strand break repair pathway. The functional loss of ATM (ATM deficiency) is hypothesised to enhance sensitivity to DDR inhibitors (DDRi). Whole-exome sequencing (WES), immunohistochemistry (IHC), and Western blotting (WB) were used to characterise the baseline ATM status across a panel of ATM mutated patient-derived xenograft (PDX) models from a range of tumour types. Antitumour efficacy was assessed with poly(ADP-ribose)polymerase (PARP, olaparib), ataxia- telangiectasia and rad3-related protein (ATR, AZD6738), and DNA-dependent protein kinase (DNA-PK, AZD7648) inhibitors as a monotherapy or in combination to associate responses with ATM status. Biallelic truncation\/frameshift ATM mutations were linked to ATM protein loss while monoallelic or missense mutations, including the clinically relevant recurrent R3008H mutation, did not confer ATM protein loss by IHC. DDRi agents showed a mixed response across the PDX\u2019s but with a general trend toward greater activity, particularly in combination in models with biallelic ATM mutation and protein loss. A PDX with an ATM splice-site mutation, 2127T &gt; C, with a high relative baseline ATM expression and KAP1 phosphorylation responded to all DDRi treatments. These data highlight the heterogeneity and complexity in describing targetable ATM-deficiencies and the fact that current patient selection biomarker methods remain imperfect; although, complete ATM loss was best able to enrich for DDRi sensitivity.<\/jats:p>","DOI":"10.3390\/cancers15164195","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T09:07:16Z","timestamp":1692608836000},"page":"4195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Relevance of ATM Status in Driving Sensitivity to DNA Damage Response Inhibitors in Patient-Derived Xenograft Models"],"prefix":"10.3390","volume":"15","author":[{"given":"Ankur","family":"Karmokar","sequence":"first","affiliation":[{"name":"Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Sargeant","sequence":"additional","affiliation":[{"name":"Imaging & Data Analytics, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adina M.","family":"Hughes","sequence":"additional","affiliation":[{"name":"Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8388-0554","authenticated-orcid":false,"given":"Hana","family":"Baakza","sequence":"additional","affiliation":[{"name":"Translational Medicine, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8811-4069","authenticated-orcid":false,"given":"Zena","family":"Wilson","sequence":"additional","affiliation":[{"name":"Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Talbot","sequence":"additional","affiliation":[{"name":"Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Bloomfield","sequence":"additional","affiliation":[{"name":"Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Leo","sequence":"additional","affiliation":[{"name":"Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma N.","family":"Jones","sequence":"additional","affiliation":[{"name":"Translational Medicine, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Likhatcheva","sequence":"additional","affiliation":[{"name":"Translational Medicine, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1947-8309","authenticated-orcid":false,"given":"Luis","family":"Tobalina","sequence":"additional","affiliation":[{"name":"Oncology Data Science, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9956-257X","authenticated-orcid":false,"given":"Emma","family":"Dean","sequence":"additional","affiliation":[{"name":"Oncology R&D, AstraZeneca, Cambridge CB2 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine B.","family":"Cadogan","sequence":"additional","affiliation":[{"name":"Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1055-9812","authenticated-orcid":false,"given":"Alan","family":"Lau","sequence":"additional","affiliation":[{"name":"Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.molcel.2015.10.040","article-title":"Targeting the DNA damage response in cancer","volume":"60","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1038\/nature03443","article-title":"Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase","volume":"434","author":"Bryant","year":"2005","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1053\/j.seminoncol.2017.08.004","article-title":"Guidance statement on BRCA1\/2 tumor testing in ovarian cancer patients","volume":"44","author":"Capoluongo","year":"2017","journal-title":"Semin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/s41573-020-0076-6","article-title":"Poly(ADP-ribose) polymerase inhibition: Past, present and future","volume":"19","author":"Curtin","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nature03445","article-title":"Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy","volume":"434","author":"Farmer","year":"2005","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1056\/NEJMoa1903387","article-title":"Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer","volume":"381","author":"Golan","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1126\/science.aam7344","article-title":"PARP inhibitors: Synthetic lethality in the clinic","volume":"355","author":"Lord","year":"2017","journal-title":"Science"},{"key":"ref_8","unstructured":"US. Food and Drug Administration (2019). FDA Approves Olaparib for gBRCAm Metastatic Pancreatic Adenocarcinoma, U.S. Food and Drug Administration."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1016\/j.dnarep.2008.08.014","article-title":"A high-throughput RNA interference screen for DNA repair determinants of PARP inhibitor sensitivity","volume":"7","author":"Lord","year":"2008","journal-title":"DNA Repair"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8109","DOI":"10.1158\/0008-5472.CAN-06-0140","article-title":"Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition","volume":"66","author":"McCabe","year":"2006","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1038\/emboj.2008.61","article-title":"A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor","volume":"27","author":"Turner","year":"2008","journal-title":"EMBO J."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Jette, N.R., Kumar, M., Radhamani, S., Arthur, G., Goutam, S., Yip, S., Kolinsky, M., Williams, G.J., Bose, P., and Lees-Miller, S.P. (2020). ATM-Deficient Cancers Provide New Opportunities for Precision Oncology. Cancers, 12.","DOI":"10.3390\/cancers12030687"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.molcel.2017.05.015","article-title":"ATM, ATR, and DNA-PK: The trinity at the heart of the DNA damage response","volume":"66","author":"Blackford","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Putti, S., Giovinazzo, A., Merolle, M., Falchetti, M.L., and Pellegrini, M. (2021). ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer. Cancers, 13.","DOI":"10.3390\/cancers13215498"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Gao, J., Aksoy, B.A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S.O., Sun, Y., Jacobsen, A., Sinha, R., and Larsson, E. (2013). Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal., 6.","DOI":"10.1126\/scisignal.2004088"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Aguilar-Quesada, R., Munoz-Gamez, J.A., Martin-Oliva, D., Peralta, A., Valenzuela, M.T., Matinez-Romero, R., Quiles-Perez, R., Menissier-de Murcia, J., de Murcia, G., and Ruiz de Almodovar, M. (2007). Interaction between ATM and PARP-1 in response to DNA damage and sensitization of ATM deficient cells through PARP inhibition. BMC Mol. Biol., 8.","DOI":"10.1186\/1471-2199-8-29"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.tranon.2017.01.007","article-title":"ATM-deficient colorectal cancer cells are sensitive to the PARP inhibitor olaparib","volume":"10","author":"Wang","year":"2017","journal-title":"Transl. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4578","DOI":"10.1182\/blood-2010-01-265769","article-title":"The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo","volume":"116","author":"Weston","year":"2010","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1002\/emmm.201200229","article-title":"Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53","volume":"4","author":"Williamson","year":"2012","journal-title":"EMBO Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/nrm2450","article-title":"ATR: An essential regulator of genome integrity","volume":"9","author":"Cimprich","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.pharmthera.2018.03.005","article-title":"Targeting the replication stress response in cancer","volume":"188","author":"Forment","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1158\/0008-5472.CAN-21-2997","article-title":"ATR inhibitor AZD6738 (ceralasertib) exerts antitumor activity as a monotherapy and in combination with chemotherapy and the PARP inhibitor olaparib","volume":"82","author":"Wilson","year":"2022","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s42764-020-00011-0","article-title":"ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738","volume":"1","author":"Jette","year":"2020","journal-title":"Genome Instab. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3040","DOI":"10.1158\/0008-5472.CAN-16-3398","article-title":"ATM deficiency is associated with sensitivity to PARP1- and ATR inhibitors in lung adenocarcinoma","volume":"77","author":"Schmitt","year":"2017","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"44289","DOI":"10.18632\/oncotarget.6247","article-title":"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","volume":"6","author":"Vendetti","year":"2015","journal-title":"Oncotarget"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Fok, J.H.L., Ramos-Montoya, A., Vazquez-Chantada, M., Wijnhoven, P.W.G., Follia, V., James, N., Farrington, P.M., Karmokar, A., Willis, S.E., and Cairns, J. (2019). AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity. Nat. Commun., 10.","DOI":"10.1038\/s41467-019-12836-9"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1182\/blood-2015-05-644872","article-title":"ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells","volume":"127","author":"Kwok","year":"2016","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4869","DOI":"10.1038\/s41388-020-1328-y","article-title":"Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells","volume":"39","author":"Lloyd","year":"2020","journal-title":"Oncogene"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1158\/1535-7163.MCT-16-0378","article-title":"AZD6738, a novel oral inhibitor of ATR, induces synthetic lethality with ATM deficiency in gastric cancer cells","volume":"16","author":"Min","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.eururo.2020.10.029","article-title":"Advanced prostate cancer with ATM loss: PARP and ATR inhibitors","volume":"79","author":"Neeb","year":"2021","journal-title":"Eur. Urol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1158\/0008-5472.CAN-19-3126","article-title":"ATM loss confers greater sensitivity to ATR inhibition than PARP inhibition in prostate cancer","volume":"80","author":"Rafiei","year":"2020","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Castroviejo-Bermejo, M., Cruz, C., Llop-Guevara, A., Guti\u00e9rrez-Enr\u00edquez, S., Ducy, M., Ibrahim, Y.H., Gris-Oliver, A., Pellegrino, B., Bruna, A., and Guzm\u00e1n, M. (2018). A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation. EMBO Mol. Med., 10.","DOI":"10.15252\/emmm.201809172"},{"key":"ref_34","unstructured":"National Library of Medicine (2022, September 13). ClinVar, Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/RCV000211973."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1182\/blood-2003-01-0094","article-title":"Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease","volume":"103","author":"Takagi","year":"2004","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"57714","DOI":"10.18632\/oncotarget.9757","article-title":"ATM protein is deficient in over 40% of lung adenocarcinomas","volume":"7","author":"Villaruz","year":"2016","journal-title":"Oncotarget"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1038\/s41416-018-0286-4","article-title":"pRAD50: A novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry","volume":"119","author":"Jones","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6159","DOI":"10.1158\/1078-0432.CCR-10-1027","article-title":"A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer","volume":"16","author":"Graeser","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1158\/0008-5472.CAN-21-2409","article-title":"Preclinical In Vivo Validation of the RAD51 Test for Identification of Homologous Recombination-Deficient Tumors and Patient Stratification","volume":"82","author":"Pellegrino","year":"2022","journal-title":"Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1470-2045(19)30684-9","article-title":"Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): A multicentre, open-label, randomised, phase 2 trial","volume":"21","author":"Mateo","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1056\/NEJMoa1911440","article-title":"Olaparib for metastatic castration-resistant prostate cancer","volume":"382","author":"Mateo","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1016\/S1470-2045(17)30682-4","article-title":"Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): A double-blind, randomised, placebo-controlled, phase 3 trial","volume":"18","author":"Bang","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1158\/2159-8290.CD-20-0868","article-title":"First-in-human trial of the oral ataxia telangiectasia and RAD3-related (ATR) inhibitor BAY 1895344 in patients with advanced solid tumors","volume":"11","author":"Yap","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Yap, T.A., Tan, D.S., Stathis, A., Shapiro, G.I., Iwasa, S., Joerger, M., Zhang, J., Plummer, R., Sawyer, M., and Tan, A.C. (2022). Phase Ib expansion trial of the safety and efficacy of the oral ataxia telangiectasia and Rad3-related (ATR) inhibitor elimusertib in advanced solid tumors with DNA damage response (DDR) defects (Abstract CT006). Cancer Res., 82.","DOI":"10.1158\/1538-7445.AM2022-CT006"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1038\/s41591-023-02399-0","article-title":"Camonsertib in DNA damage response-deficient advanced solid tumors: Phase 1 trial results","volume":"29","author":"Yap","year":"2023","journal-title":"Nat. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1158\/2767-9764.CRC-22-0119","article-title":"Drug\u2013gene Interaction Screens Coupled to Tumor Data Analyses Identify the Most Clinically Relevant Cancer Vulnerabilities Driving Sensitivity to PARP Inhibition","volume":"2","author":"Jamal","year":"2022","journal-title":"Cancer Res. Commun."},{"key":"ref_47","unstructured":"ClinicalTrials.gov (2023, May 31). A Study Investigating DNA-Damage Response Agents in Molecularly Altered Advanced Cancer, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04564027."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/16\/4195\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:38:40Z","timestamp":1760128720000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/16\/4195"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,21]]},"references-count":47,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["cancers15164195"],"URL":"https:\/\/doi.org\/10.3390\/cancers15164195","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,21]]}}}