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Novel total neoadjuvant treatment (TNT) in rectal cancer has achieved pathological complete response in one-third of the patients. To define better treatment options for nonresponding patients, we used patient-derived organoids (PDOs) as avatars of the patient\u2019s tumor to apply both photon- and proton-based irradiation as well as single and combined chemo(radio)therapeutic treatments. While response to photon and proton therapy was similar, PDOs revealed heterogeneous responses to irradiation and different chemotherapeutic drugs. Radiotherapeutic response of the PDOs was significantly correlated with their ability to repair irradiation-induced DNA damage. The classical combination of 5-FU and irradiation could not sensitize radioresistant tumor cells. Ataxia-telangiectasia mutated (ATM) kinase was activated upon radiation, and by inhibition of this central sensor of DNA damage, radioresistant PDOs were resensitized. The study underlined the capability of PDOs to define nonresponders to irradiation and could delineate therapeutic approaches for radioresistant patients.<\/jats:p>","DOI":"10.3390\/cancers14204984","type":"journal-article","created":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T22:18:13Z","timestamp":1665526693000},"page":"4984","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Sensitization of Patient-Derived Colorectal Cancer Organoids to Photon and Proton Radiation by Targeting DNA Damage Response Mechanisms"],"prefix":"10.3390","volume":"14","author":[{"given":"Kristin","family":"Pape","sequence":"first","affiliation":[{"name":"Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine Carl Gustav Carus, University Hospital, Technische Universit\u00e4t Dresden, 01307 Dresden, Germany"},{"name":"National Center for Tumor Diseases (NCT\/UCC), German Cancer Research Center (DKFZ), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna J.","family":"L\u00f6\u00dfner","sequence":"additional","affiliation":[{"name":"Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine Carl Gustav Carus, University Hospital, Technische Universit\u00e4t Dresden, 01307 Dresden, Germany"},{"name":"National Center for Tumor Diseases (NCT\/UCC), German Cancer Research Center (DKFZ), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7824-5073","authenticated-orcid":false,"given":"Doreen","family":"William","sequence":"additional","affiliation":[{"name":"Core Unit for Molecular 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