{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T10:44:38Z","timestamp":1781174678475,"version":"3.54.1"},"reference-count":43,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,4,30]],"date-time":"2020-04-30T00:00:00Z","timestamp":1588204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CPII18\/00026"],"award-info":[{"award-number":["CPII18\/00026"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI14\/00783"],"award-info":[{"award-number":["PI14\/00783"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI17\/01304"],"award-info":[{"award-number":["PI17\/01304"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003030","name":"Ag\u00e8ncia de Gesti\u00f3 d'Ajuts Universitaris i de Recerca","doi-asserted-by":"publisher","award":["2017 SGR 1035"],"award-info":[{"award-number":["2017 SGR 1035"]}],"id":[{"id":"10.13039\/501100003030","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fundaci\u00f3n Cient\u00edfica de la Asociaci\u00f3n Espa\u00f1ola Contra el C\u00e1ncer","award":["GCB13131592CAST"],"award-info":[{"award-number":["GCB13131592CAST"]}]},{"DOI":"10.13039\/501100000921","name":"European Cooperation in Science and Technology","doi-asserted-by":"publisher","award":["CA17118"],"award-info":[{"award-number":["CA17118"]}],"id":[{"id":"10.13039\/501100000921","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["Intramural"],"award-info":[{"award-number":["Intramural"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Tetraploidy, or whole-genome duplication, is a common phenomenon in cancer and preludes chromosome instability, which strongly correlates with disease progression, metastasis, and treatment failure. Therefore, it is reasonable to hypothesize that tetraploidization confers multidrug resistance. Nevertheless, the contribution of whole-genome duplication to chemo-radiotherapy resistance remains unclear. Here, using isogenic diploid and near-tetraploid clones from three colorectal cancer cell lines and one non-transformed human epithelial cell line, we show a consistent growth impairment but a divergent tumorigenic potential of near-tetraploid cells. Next, we assessed the effects of first-line chemotherapeutic drugs, other commonly used agents and ionizing radiation, and found that whole-genome duplication promoted increased chemotherapy resistance and also conferred protection against irradiation. When testing the activation of apoptosis, we observed that tetraploid cells were less prone to caspase 3 activation after treatment with first-line chemotherapeutic agents. Furthermore, we found that pre-treatment with ataxia telangiectasia and Rad3 related (ATR) inhibitors, which targets response to replication stress, significantly enhanced the sensitivity of tetraploid cells to first-line chemotherapeutic agents as well as to ionizing radiation. Our findings provide further insight into how tetraploidy results in greater levels of tolerance to chemo-radiotherapeutic agents and, moreover, we show that ATR inhibitors can sensitize near-tetraploid cells to commonly used chemo-radiotherapy regimens.<\/jats:p>","DOI":"10.3390\/cancers12051118","type":"journal-article","created":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T06:41:20Z","timestamp":1588660880000},"page":"1118","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4415-4987","authenticated-orcid":false,"given":"Claudia","family":"Galofr\u00e9","sequence":"first","affiliation":[{"name":"Gastrointestinal and Pancreatic Oncology Team, Institut D\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Hospital Cl\u00ednic de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6yk\u00fc","family":"G\u00f6n\u00fcl Geyik","sequence":"additional","affiliation":[{"name":"Section for Cancer Genomics, Genetics Branch, National Cancer Institute, National Institute of Health, Bethesda, MD 20817, USA"},{"name":"Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, 35330 Izmir, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Asensio","sequence":"additional","affiliation":[{"name":"Gastrointestinal and Pancreatic Oncology Team, Institut D\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Hospital Cl\u00ednic de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darawalee","family":"Wangsa","sequence":"additional","affiliation":[{"name":"Section for Cancer Genomics, Genetics Branch, National Cancer Institute, National Institute of Health, Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8883-922X","authenticated-orcid":false,"given":"Daniela","family":"Hirsch","sequence":"additional","affiliation":[{"name":"Section for Cancer Genomics, Genetics Branch, National Cancer Institute, National Institute of Health, Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Parra","sequence":"additional","affiliation":[{"name":"Gastrointestinal and Pancreatic Oncology Team, Institut D\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Hospital Cl\u00ednic de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Saez","sequence":"additional","affiliation":[{"name":"Radiation Oncology Department, Hospital Cl\u00ednic de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meritxell","family":"Moll\u00e0","sequence":"additional","affiliation":[{"name":"Radiation Oncology Department, Hospital Cl\u00ednic de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeynep","family":"Y\u00fcce","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, 35330 Izmir, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8431-2033","authenticated-orcid":false,"given":"Antoni","family":"Castells","sequence":"additional","affiliation":[{"name":"Gastrointestinal and Pancreatic Oncology Team, Institut D\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Hospital Cl\u00ednic de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Ried","sequence":"additional","affiliation":[{"name":"Section for Cancer Genomics, Genetics Branch, National Cancer Institute, National Institute of Health, Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2929-4228","authenticated-orcid":false,"given":"Jordi","family":"Camps","sequence":"additional","affiliation":[{"name":"Gastrointestinal and Pancreatic Oncology Team, Institut D\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Hospital Cl\u00ednic de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), 08036 Barcelona, Spain"},{"name":"Unitat de Biologia Cel\u00b7lular i Gen\u00e8tica M\u00e8dica, Departament de Biologia Cel\u00b7lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1038\/ng.2760","article-title":"Pan-cancer patterns of somatic copy number alteration","volume":"45","author":"Zack","year":"2013","journal-title":"Nat. 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