{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:28:33Z","timestamp":1792114113289,"version":"4.4.0"},"reference-count":152,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Salud Carlos III (ISCIII)-FIS Pl25\/01059","award":["240390"],"award-info":[{"award-number":["240390"]}]},{"name":"World Wide Cancer Research","award":["240390"],"award-info":[{"award-number":["240390"]}]},{"name":"Gobierno de Navarra-GRANATE","award":["240390"],"award-info":[{"award-number":["240390"]}]},{"name":"International Association for the Study of Lung Cancer","award":["240390"],"award-info":[{"award-number":["240390"]}]},{"name":"Asociaci\u00f3n de Amigos, University of Navarra","award":["240390"],"award-info":[{"award-number":["240390"]}]},{"name":"Gobierno de Navarra","award":["240390"],"award-info":[{"award-number":["240390"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Eliciting DNA damage in tumor cells continues to be one of the most successful strategies against cancer. This is the case for classical chemotherapy drugs and radiotherapy. In the modern era of personalized medicine, this strategy tries to identify specific vulnerabilities found in each patient\u2019s tumor, to inflict DNA damage in certain cell contexts that end up in massive cancer cell death. Cells rely on multiple DNA repair pathways to fix DNA damage, but cancer cells frequently exhibit defects in these pathways, many times being tolerant to the damage. Key vulnerabilities, such as BRCA1\/BRCA2 mutations, have been exploited with PARP inhibitors, leveraging synthetic lethality to selectively kill tumor cells and improving patients\u2019 survival. In the DNA damage response (DDR) network, kinases ATM, ATR, Chk1, and Chk2 coordinate DNA repair, cell cycle arrest, and apoptosis. Inhibiting these proteins enhances tumor sensitivity to DNA-damaging therapies, especially in DDR-deficient cancers. Several small-molecule inhibitors targeting ATM\/Chk2 or ATR\/Chk1 are currently being tested in preclinical and\/or clinical settings, showing promise in cancer models and patients. Additionally, pharmacological blockade of ATM\/Chk2 and ATR\/Chk1 axes enhances the effects of immunotherapy by increasing tumor immunogenicity, promoting T-cell infiltration and activating immune responses. Combining ATM\/Chk2- or ATR\/Chk1-targeting drugs with conventional chemotherapy, radiotherapy or immune checkpoint inhibitors offers a compelling strategy to improve treatment efficacy, overcome resistance, and enhance patients\u2019 survival in modern oncology.<\/jats:p>","DOI":"10.3390\/cells14100748","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T09:33:47Z","timestamp":1747733627000},"page":"748","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Cancer Vulnerabilities Through Targeting the ATR\/Chk1 and ATM\/Chk2 Axes in the Context of DNA Damage"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7210-2321","authenticated-orcid":false,"given":"Anell","family":"Fernandez","sequence":"first","affiliation":[{"name":"Program in Solid Tumors, CIMA, Cancer Center Clinica Universidad de Navarra (CCUN), University of Navarra, Avenida de Pio XII, 55, 31008 Pamplona, Spain"},{"name":"Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maider","family":"Artola","sequence":"additional","affiliation":[{"name":"Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Leon","sequence":"additional","affiliation":[{"name":"Program in Solid Tumors, CIMA, Cancer Center Clinica Universidad de Navarra (CCUN), University of Navarra, Avenida de Pio XII, 55, 31008 Pamplona, Spain"},{"name":"Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain"},{"name":"CIBERONC, ISCIII, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7470-0847","authenticated-orcid":false,"given":"Nerea","family":"Otegui","sequence":"additional","affiliation":[{"name":"Program in Solid Tumors, CIMA, Cancer Center Clinica Universidad de Navarra (CCUN), University of Navarra, Avenida de Pio XII, 55, 31008 Pamplona, Spain"},{"name":"Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain"},{"name":"CIBERONC, ISCIII, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aroa","family":"Jimeno","sequence":"additional","affiliation":[{"name":"Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3729-9195","authenticated-orcid":false,"given":"Diego","family":"Serrano","sequence":"additional","affiliation":[{"name":"Program in Solid Tumors, CIMA, Cancer Center Clinica Universidad de Navarra (CCUN), University of Navarra, Avenida de Pio XII, 55, 31008 Pamplona, Spain"},{"name":"Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain"},{"name":"CIBERONC, ISCIII, 28029 Madrid, Spain"},{"name":"IDISNA, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4074-4242","authenticated-orcid":false,"given":"Alfonso","family":"Calvo","sequence":"additional","affiliation":[{"name":"Program in Solid Tumors, CIMA, Cancer Center Clinica Universidad de Navarra (CCUN), University of Navarra, Avenida de Pio XII, 55, 31008 Pamplona, Spain"},{"name":"Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain"},{"name":"CIBERONC, ISCIII, 28029 Madrid, Spain"},{"name":"IDISNA, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Baskar, R., Dai, J., Wenlong, N., Yeo, R., and Yeoh, K.W. 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