{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T14:39:49Z","timestamp":1791470389424,"version":"4.3.4"},"reference-count":190,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic cancer (PC) remains a highly lethal malignancy with limited treatment options and poor survival. Targeting DNA damage response (DDR) pathways has emerged as a promising therapeutic strategy, particularly the ATR-CHK1 and ATM-CHK2 axes. Preclinical studies demonstrate that ATR inhibition disrupts replication stress tolerance, impairs homologous recombination, and disables checkpoint control, enhancing cytotoxicity from standard therapies including gemcitabine, FOLFIRINOX, fluoropyrimidines, and radiotherapy. Synergistic effects have also been observed with other DDR-targeted agents, such as PARP and WEE1 inhibitors. Genomic contexts, including ATM deficiency, ARID1A alterations, and oncogene-driven replication stress, refine therapeutic sensitivity, supporting precision patient stratification. Early-phase clinical trials of ATR inhibitors (ART0380, AZD6738, BBI-355) alone or in combination show promising safety, tolerability, and preliminary efficacy. In this review, we summarize current literature on targeting the ATM-CHK2 and ATR-CHK1 pathways in PC, highlighting preclinical evidence, clinical developments, and strategies for biomarker-driven, precision oncology approaches.<\/jats:p>","DOI":"10.3390\/ijms27031152","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T10:41:34Z","timestamp":1769164894000},"page":"1152","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeting ATR-CHK1 and ATM-CHK2 Axes in Pancreatic Cancer\u2014A Comprehensive Review of Literature"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8616-3825","authenticated-orcid":false,"given":"Mateusz","family":"Kciuk","sequence":"first","affiliation":[{"name":"Department of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, Poland"},{"name":"Department of Functional Genomics, Medical University of Lodz, 90-752 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9010-8493","authenticated-orcid":false,"given":"Katarzyna","family":"Wanke","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata","family":"Marciniak","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1086-3796","authenticated-orcid":false,"given":"Damian","family":"Ko\u0142at","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, Poland"},{"name":"Department of Functional Genomics, Medical University of Lodz, 90-752 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1922-7662","authenticated-orcid":false,"given":"Marta","family":"Aleksandrowicz","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 A. Pawi\u0144skiego Street, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4037-5475","authenticated-orcid":false,"given":"Somdutt","family":"Mujwar","sequence":"additional","affiliation":[{"name":"Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6743-2666","authenticated-orcid":false,"given":"Tarik","family":"Ainane","sequence":"additional","affiliation":[{"name":"Superior School of Technology of Khenifra, University of Sultan Moulay Slimane, P.O. Box 170, Khenifra 54000, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2859-9839","authenticated-orcid":false,"given":"Renata","family":"Kontek","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Li, T., Lin, C., and Wang, W. (2025). Global, Regional, and National Burden of Pancreatic Cancer from 1990 to 2021, Its Attributable Risk Factors, and Projections to 2050: A Systematic Analysis of the Global Burden of Disease Study 2021. 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