{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:10:30Z","timestamp":1760163030077,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T00:00:00Z","timestamp":1616371200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006313","name":"Barncancerfonden","doi-asserted-by":"publisher","award":["TJ2019-0020, PR-2019-0047"],"award-info":[{"award-number":["TJ2019-0020, PR-2019-0047"]}],"id":[{"id":"10.13039\/501100006313","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007435","name":"\u00c5ke Wiberg Stiftelse","doi-asserted-by":"publisher","award":["M19-0435, M18-0098"],"award-info":[{"award-number":["M19-0435, M18-0098"]}],"id":[{"id":"10.13039\/100007435","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006285","name":"Magnus Bergvalls Stiftelse","doi-asserted-by":"publisher","award":["2018-02983, 2019-03364"],"award-info":[{"award-number":["2018-02983, 2019-03364"]}],"id":[{"id":"10.13039\/501100006285","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["722729"],"award-info":[{"award-number":["722729"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The C-X3-C motif chemokine receptor 1 (CX3CR1, fractalkine receptor) is associated with neoplastic transformation, inflammation, neurodegenerative diseases and aging, and the small molecule inhibitor KAND567 targeting CX3CR1 (CX3CR1i) is evaluated in clinical trials for acute systemic inflammation upon SARS-CoV-2 infections. Here we identify a hitherto unknown role of CX3CR1 in Fanconi anemia (FA) pathway mediated repair of DNA interstrand crosslinks (ICLs) in replicating cells. FA pathway activation triggers CX3CR1 nuclear localization which facilitates assembly of the key FA protein FANCD2 into foci. Interfering with CX3CR1 function upon ICL-induction results in inability of replicating cells to progress from S phase, replication fork stalling and impaired chromatin recruitment of key FA pathway factors. Consistent with defective FA repair, CX3CR1i results in increased levels of residual cisplatin-DNA adducts and decreased cell survival. Importantly, CX3CR1i synergizes with platinum agents in a nonreversible manner in proliferation assays including platinum resistant models. Taken together, our results reveal an unanticipated interplay between CX3CR1 and the FA pathway and show for the first time that a clinical-phase small molecule inhibitor targeting CX3CR1 might show benefit in improving responses to DNA crosslinking chemotherapeutics.<\/jats:p>","DOI":"10.3390\/cancers13061442","type":"journal-article","created":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T11:13:26Z","timestamp":1616411606000},"page":"1442","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Targeting CX3CR1 Suppresses the Fanconi Anemia DNA Repair Pathway and Synergizes with Platinum"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2827-5749","authenticated-orcid":false,"given":"Jemina","family":"Lehto","sequence":"first","affiliation":[{"name":"Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institute, 171 21 Stockholm, Sweden"},{"name":"Kancera AB, Karolinska Science Park, 171 48 Solna, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Huguet Ninou","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institute, 171 21 Stockholm, Sweden"},{"name":"Kancera AB, Karolinska Science Park, 171 48 Solna, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitrios","family":"Chioureas","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institute, 171 21 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos","family":"Jonkers","sequence":"additional","affiliation":[{"name":"Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6401-0548","authenticated-orcid":false,"given":"Nina M. S.","family":"Gustafsson","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institute, 171 21 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/nrc3088","article-title":"DNA interstrand crosslink repair and cancer","volume":"11","author":"Deans","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1146\/annurev-cancerbio-030617-050422","article-title":"The fanconi anemia pathway in cancer","volume":"3","author":"Niraj","year":"2019","journal-title":"Annu. Rev. 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