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DNA damage response (DDR) inhibitors are a\u00a0promising drug class, especially in combination with chemotherapy (CT) or radiotherapy (RT). Manipulating DNA damage repair during RT is an opportunity to exploit the genomic instability of cancer cells and may lead to radiosensitizing effects in tumors that could improve cancer therapy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>A\u00a0panel of melanoma-derived cell lines of different origin were used to investigate toxicity-related clonogenic survival, cell death, and cell cycle distribution after treatment with a\u00a0kinase inhibitor (KI) against ATM (AZD0156) or ATR (VE-822, berzosertib), irradiation with 2\u202fGy, or a\u00a0combination of KI plus ionizing radiation (IR). Two fibroblast cell lines generated from healthy skin tissue were used as controls.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Clonogenic survival indicated a\u00a0clear radiosensitizing effect of the ATM inhibitor (ATMi) AZD0156 in all melanoma cells in a\u00a0synergistic manner, but not in healthy tissue fibroblasts. In contrast, the ATR inhibitor (ATRi) VE-822 led to additive enhancement of IR-related toxicity in most of the melanoma cells. Both inhibitors mainly increased cell death induction in combination with IR. In healthy fibroblasts, VE-822 plus IR led to higher cell death rates compared to AZD0156. A\u00a0significant G2\/M block was particularly induced in cancer cells when combining AZD0156 with IR.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>ATMi, in contrast to ATRi, resulted in synergistic radiosensitization regarding colony formation in melanoma cancer cells, while healthy tissue fibroblasts were merely affected with respect to cell death induction. In connection with an increased number of melanoma cells in the G2\/M phase after ATMi plus IR treatment, ATMi seems to be superior to ATRi in melanoma cancer cell treatments when combined with RT.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00066-022-02009-x","type":"journal-article","created":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T16:02:30Z","timestamp":1665676950000},"page":"1128-1139","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Tumor-specific radiosensitizing effect of the ATM inhibitor AZD0156 in melanoma cells with low toxicity to healthy fibroblasts"],"prefix":"10.1007","volume":"199","author":[{"given":"Julian","family":"Scheper","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1522-9591","authenticated-orcid":false,"given":"Laura S.","family":"Hildebrand","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva-Maria","family":"Faulhaber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5577-2302","authenticated-orcid":false,"given":"Lisa","family":"Deloch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6375-5476","authenticated-orcid":false,"given":"Udo S.","family":"Gaipl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Symank","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rainer","family":"Fietkau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8040-3226","authenticated-orcid":false,"given":"Luitpold V.","family":"Distel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2082-216X","authenticated-orcid":false,"given":"Markus","family":"Hecht","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8767-3774","authenticated-orcid":false,"given":"Tina","family":"Jost","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,10,13]]},"reference":[{"key":"2009_CR1","doi-asserted-by":"publisher","first-page":"e101801","DOI":"10.15252\/embj.2019101801","volume":"38","author":"MC Lanz","year":"2019","unstructured":"Lanz\u00a0MC, Dibitetto\u00a0D, Smolka\u00a0MB (2019) DNA damage kinase signaling: checkpoint and repair at 30\u00a0years. 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U.\u00a0S.\u00a0Gaipl received support for presentation activities for Dr Sennewald Medizintechnik GmbH, has received support for investigator-initiated clinical studies (IITs) from MSD and AstraZeneca, and contributed at advisory boards meetings of AstraZeneca and Bristol-Myers Squibb. J.\u00a0Scheper, L.\u00a0S.\u00a0Hildebrand, E.-M.\u00a0Faulhaber, L.\u00a0Deloch, J.\u00a0Symank, R.\u00a0Fietkau, L.V.\u00a0Distel, and T.\u00a0Jost declare that they have no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All procedures performed in studies involving human participants or on human tissue were in accordance with the ethical standards of the institutional and\/or national research committee and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical standards"}}]}}