{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:17:00Z","timestamp":1790788620075,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,16]],"date-time":"2020-09-16T00:00:00Z","timestamp":1600214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["111879"],"award-info":[{"award-number":["111879"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["KL 2544\/1-1, 1-2, 5-1, 7-1"],"award-info":[{"award-number":["KL 2544\/1-1, 1-2, 5-1, 7-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["KL 2544\/6-1"],"award-info":[{"award-number":["KL 2544\/6-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008316","name":"Baden-W\u00fcrttemberg Stiftung","doi-asserted-by":"publisher","award":["ExPoChip"],"award-info":[{"award-number":["ExPoChip"]}],"id":[{"id":"10.13039\/100008316","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["INDIMED-Verbund PancChip"],"award-info":[{"award-number":["INDIMED-Verbund PancChip"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius-Stiftung","doi-asserted-by":"publisher","award":["LSBN.0149"],"award-info":[{"award-number":["LSBN.0149"]}],"id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Personalized medicine in treating pancreatic ductal adenocarcinoma (PDAC) is still in its infancy, albeit PDAC-related deaths are projected to rise over the next decade. Only recently, maintenance therapy with the PARP inhibitor olaparib showed improved progression-free survival in germline BRCA1\/2-mutated PDAC patients after platinum-based induction for the first time. Transferability of such a concept to other DNA damage response (DDR) genes remains unclear. Here, we conducted a placebo-controlled, three-armed preclinical trial to evaluate the efficacy of multi-DDR interference (mDDRi) as maintenance therapy vs. continuous FOLFIRINOX treatment, implemented with orthotopically transplanted ATM-deficient PDAC cell lines. Kaplan\u2013Meier analysis, cross-sectional imaging, histology, and in vitro analysis served as analytical readouts. Median overall survival was significantly longer in the mDDRi maintenance arm compared to the maintained FOLFIRINOX treatment. This survival benefit was mirrored in the highest DNA-damage load, accompanied by superior disease control and reduced metastatic burden. In vitro analysis suggests FOLFIRINOX-driven selection of invasive subclones, erased by subsequent mDDRi treatment. Collectively, this preclinical trial substantiates mDDRi in a maintenance setting as a novel therapeutic option and extends the concept to non-germline BRCA1\/2-mutant PDAC.<\/jats:p>","DOI":"10.3390\/cells9092110","type":"journal-article","created":{"date-parts":[[2020,9,16]],"date-time":"2020-09-16T20:44:13Z","timestamp":1600289053000},"page":"2110","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4930-6292","authenticated-orcid":false,"given":"Elodie","family":"Roger","sequence":"first","affiliation":[{"name":"Department of Internal Medicine 1, University Medical Center Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0522-9800","authenticated-orcid":false,"given":"Johann","family":"Gout","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 1, University Medical Center Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Arnold","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 1, University Medical Center Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alica K.","family":"Beutel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 1, University Medical Center Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 1, University Medical Center Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Abaei","sequence":"additional","affiliation":[{"name":"Center for Translational Imaging (MoMAN), Ulm University, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F. E.","family":"Barth","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Medical Center Ulm, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8844-3583","authenticated-orcid":false,"given":"Volker","family":"Rasche","sequence":"additional","affiliation":[{"name":"Center for Translational Imaging (MoMAN), Ulm University, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Seufferlein","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 1, University Medical Center Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Perkhofer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 1, University Medical Center Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0592-5232","authenticated-orcid":false,"given":"Alexander","family":"Kleger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 1, University Medical Center Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0140-6736(16)00141-0","article-title":"Pancreatic cancer","volume":"388","author":"Kamisawa","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1093\/annonc\/mdu013","article-title":"Smarter drugs emerging in pancreatic cancer therapy","volume":"25","author":"Kleger","year":"2014","journal-title":"Ann. Oncol"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1056\/NEJMoa1011923","article-title":"FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer","volume":"364","author":"Conroy","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1056\/NEJMoa1304369","article-title":"Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine","volume":"369","author":"Ervin","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1158\/2159-8290.CD-18-0275","article-title":"Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine","volume":"8","author":"Aguirre","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/nature14169","article-title":"Whole genomes redefine the mutational landscape of pancreatic cancer","volume":"518","author":"Waddell","year":"2015","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/s41436-018-0009-5","article-title":"Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer","volume":"21","author":"Yurgelun","year":"2019","journal-title":"Genet. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1053\/j.gastro.2018.11.071","article-title":"DNA Mismatch Repair Deficiency and Immune Checkpoint Inhibitors in Gastrointestinal Cancers","volume":"156","author":"Goel","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M.J., Park, J.O., Hochhauser, D., Arnold, D., and Oh, D.Y. (2019). Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N. Engl. J. Med.","DOI":"10.1056\/NEJMoa1903387"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Park, W., Chen, J., Chou, J.F., Varghese, A.M., Yu, K.H., Wong, W., Capanu, M., Balachandran, V., McIntyre, C.A., and El Dika, I. (2020). Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection. Clin. Cancer Res.","DOI":"10.1158\/1078-0432.CCR-20-0418"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Perkhofer, L., Gout, J., Roger, E., Kude de Almeida, F., Baptista Simoes, C., Wiesmuller, L., Seufferlein, T., and Kleger, A. (2020). DNA damage repair as a target in pancreatic cancer: State-of-the-art and future perspectives. Gut.","DOI":"10.1136\/gutjnl-2019-319984"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Gout, J., Perkhofer, L., Morawe, M., Arnold, F., Ihle, M., Biber, S., Lange, S., Roger, E., Kraus, J.M., and Stifter, K. (2020). Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer. Gut.","DOI":"10.1055\/s-0040-1716086"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6","DOI":"10.18632\/oncoscience.392","article-title":"Precision medicine meets the DNA damage response in pancreatic cancer","volume":"5","author":"Perkhofer","year":"2018","journal-title":"Oncoscience"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7677","DOI":"10.1038\/ncomms8677","article-title":"Loss of ATM accelerates pancreatic cancer formation and epithelial-mesenchymal transition","volume":"6","author":"Russell","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5576","DOI":"10.1158\/0008-5472.CAN-17-0634","article-title":"ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage","volume":"77","author":"Perkhofer","year":"2017","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1093\/annonc\/mdu187","article-title":"Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors","volume":"25","author":"Balmana","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1200\/JCO.19.02931","article-title":"Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin with or without Veliparib in Patients with Pancreas Adenocarcinoma and a Germline BRCA\/PALB2 Mutation","volume":"38","author":"Lee","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lloyd, R.L., Wijnhoven, P.W.G., Ramos-Montoya, A., Wilson, Z., Illuzzi, G., Falenta, K., Jones, G.N., James, N., Chabbert, C.D., and Stott, J. (2020). Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells. Oncogene.","DOI":"10.1038\/s41388-020-1328-y"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"189ra78","DOI":"10.1126\/scitranslmed.3005814","article-title":"Therapeutic Targeting of a Robust Non-Oncogene Addiction to PRKDC in ATM-Defective Tumors","volume":"5","author":"Riabinska","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/j.molcel.2015.07.029","article-title":"Distinct but Concerted Roles of ATR, DNA-PK, and Chk1 in Countering Replication Stress during S Phase","volume":"59","author":"Buisson","year":"2015","journal-title":"Mol. Cell."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9302","DOI":"10.1073\/pnas.0803520105","article-title":"Complementary functions of ATM and H2AX in development and suppression of genomic instability","volume":"105","author":"Zha","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3243","DOI":"10.1101\/gad.943001","article-title":"Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras","volume":"15","author":"Jackson","year":"2001","journal-title":"Genes Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/ng959","article-title":"The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors","volume":"32","author":"Kawaguchi","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Erstad, D.J., Sojoodi, M., Taylor, M.S., Ghoshal, S., Razavi, A.A., Graham-O\u2019Regan, K.A., Bardeesy, N., Ferrone, C.R., Lanuti, M., and Caravan, P. (2018). Orthotopic and heterotopic murine models of pancreatic cancer and their different responses to FOLFIRINOX chemotherapy. Dis Model. Mech., 11.","DOI":"10.1242\/dmm.034793"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)","volume":"45","author":"Eisenhauer","year":"2009","journal-title":"Eur. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/nrclinonc.2013.66","article-title":"Advanced-stage pancreatic cancer: Therapy options","volume":"10","author":"Werner","year":"2013","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1101\/gad.1158703","article-title":"Activated Kras and Ink4a\/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma","volume":"17","author":"Aguirre","year":"2003","journal-title":"Genes Dev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1158\/2159-8290.CD-15-0402","article-title":"Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer","volume":"6","author":"Roberts","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kieler, M., Unseld, M., Bianconi, D., Schindl, M., Kornek, G.V., Scheithauer, W., and Prager, G.W. (2020). Impact of New Chemotherapy Regimens on the Treatment Landscape and Survival of Locally Advanced and Metastatic Pancreatic Cancer Patients. J. Clin. Med., 9.","DOI":"10.3390\/jcm9030648"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Vogl, U.M., Andalibi, H., Klaus, A., Vormittag, L., Schima, W., Heinrich, B., Kafka, A., Winkler, T., and Ohler, L. (2019). Nab-paclitaxel and gemcitabine or FOLFIRINOX as first-line treatment in patients with unresectable adenocarcinoma of the pancreas: Does sequence matter?. BMC Cancer, 19.","DOI":"10.1186\/s12885-018-5240-6"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"a026617","DOI":"10.1101\/cshperspect.a026617","article-title":"Treatment-Induced Mutagenesis and Selective Pressures Sculpt Cancer Evolution","volume":"7","author":"Venkatesan","year":"2017","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8","DOI":"10.7554\/eLife.45313","article-title":"Transcriptional control of subtype switching ensures adaptation and growth of pancreatic cancer","volume":"8","author":"Adams","year":"2019","journal-title":"Elife"},{"key":"ref_34","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_35","doi-asserted-by":"crossref","first-page":"74688","DOI":"10.18632\/oncotarget.20342","article-title":"CC-115, a dual inhibitor of mTOR kinase and DNA-PK, blocks DNA damage repair pathways and selectively inhibits ATM-deficient cell growth in vitro","volume":"8","author":"Tsuji","year":"2017","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ccell.2018.12.010","article-title":"Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases","volume":"35","author":"Connor","year":"2019","journal-title":"Cancer Cell"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/9\/2110\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:10:42Z","timestamp":1760177442000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/9\/2110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,16]]},"references-count":36,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["cells9092110"],"URL":"https:\/\/doi.org\/10.3390\/cells9092110","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,16]]}}}