{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:59:16Z","timestamp":1790189956556,"version":"4.1.0"},"reference-count":72,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"39","funder":[{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["DEQ20170839117"],"award-info":[{"award-number":["DEQ20170839117"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004431","name":"Fondation de France","doi-asserted-by":"publisher","award":["00097702"],"award-info":[{"award-number":["00097702"]}],"id":[{"id":"10.13039\/501100004431","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004431","name":"Fondation de France","doi-asserted-by":"publisher","award":["00113878"],"award-info":[{"award-number":["00113878"]}],"id":[{"id":"10.13039\/501100004431","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004431","name":"Fondation de France","doi-asserted-by":"publisher","award":["00119148"],"award-info":[{"award-number":["00119148"]}],"id":[{"id":"10.13039\/501100004431","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006364","name":"Institut National Du Cancer","doi-asserted-by":"publisher","award":["INCA_16730"],"award-info":[{"award-number":["INCA_16730"]}],"id":[{"id":"10.13039\/501100006364","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006364","name":"Institut National Du Cancer","doi-asserted-by":"publisher","award":["INCA_19472"],"award-info":[{"award-number":["INCA_19472"]}],"id":[{"id":"10.13039\/501100006364","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,9,25]]},"abstract":"<jats:p>\n                    Resistance to targeted cancer therapies often arises from drug-tolerant cells, which survive treatment by entering a nonproliferative state. Over time, these cells can acquire mutations that contribute to cell reproliferation, but how nonproliferating drug-tolerant cells accumulate these mutations remains unclear. Here, we show that EGFR inhibition in\n                    <jats:italic toggle=\"yes\">EGFR<\/jats:italic>\n                    -mutated lung cancer transiently down-regulates tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme that resolves abortive topoisomerase I cleavage complexes (TOP1ccs). In drug-tolerant cells, elevated reactive oxygen species promote TOP1cc trapping, while TDP1 down-regulation impairs their repair, driving TOP1cc accumulation, resistance mutation acquisition, and cell reproliferation. We further find that TDP1 expression is absent in \u223c25% of\n                    <jats:italic toggle=\"yes\">EGFR<\/jats:italic>\n                    -mutated lung cancers. In TDP1-deficient cells, combining EGFR inhibition with a sublethal concentration of topotecan, which further increases TOP1ccs, abolishes cell reproliferation. Together, these findings establish persistent TOP1cc accumulation as a driver of therapy-induced mutagenesis linking drug tolerance to adaptive resistance and reveal TDP1 loss as a targetable vulnerability in EGFR-mutated lung cancers.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeh9099","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T17:59:49Z","timestamp":1790186389000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Persistent TOP1 cleavage complexes in drug-tolerant cells drive adaptive resistance to EGFR-targeted therapies in lung cancer"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6879-0588","authenticated-orcid":true,"given":"Math\u00e9a","family":"Geraud","sequence":"first","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."},{"name":"Laboratoire de Biologie M\u00e9dicale Oncologique, Oncopole Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0747-3540","authenticated-orcid":true,"given":"Remi","family":"Gence","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Casanova","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."},{"name":"Laboratoire de Biologie M\u00e9dicale Oncologique, Oncopole Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estelle","family":"Taranchon-Clermont","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."},{"name":"Centre Hospitalier Universitaire (CHU) de Toulouse, service de pneumologie, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Salimbeni","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nesibe","family":"\u00d6zsu","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maina","family":"Vienne","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7966-5597","authenticated-orcid":true,"given":"C\u00e9lia","family":"Delahaye","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"Borrull","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9691-5536","authenticated-orcid":true,"given":"Am\u00e9lie","family":"Lusque","sequence":"additional","affiliation":[{"name":"University of Toulouse, Oncopole Claudius Regaud, IUCT-Oncopole, Biostatistics &amp; Health Data Science Unit, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathilde","family":"Morisseau","sequence":"additional","affiliation":[{"name":"University of Toulouse, Oncopole Claudius Regaud, IUCT-Oncopole, Biostatistics &amp; Health Data Science Unit, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Filleron","sequence":"additional","affiliation":[{"name":"University of Toulouse, Oncopole Claudius Regaud, IUCT-Oncopole, Biostatistics &amp; Health Data Science Unit, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8298-3682","authenticated-orcid":true,"given":"Delphine","family":"Pagan","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Taha","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0235-8770","authenticated-orcid":true,"given":"Agnese","family":"Cristini","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5921-7613","authenticated-orcid":true,"given":"Julien","family":"Mazi\u00e8res","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."},{"name":"Centre Hospitalier Universitaire (CHU) de Toulouse, service de pneumologie, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0908-8323","authenticated-orcid":true,"given":"Olivier","family":"Calvayrac","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2344-1883","authenticated-orcid":true,"given":"Gilles","family":"Favre","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."},{"name":"Laboratoire de Biologie M\u00e9dicale Oncologique, Oncopole Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2449-678X","authenticated-orcid":true,"given":"Anne","family":"Pradines","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."},{"name":"Laboratoire de Biologie M\u00e9dicale Oncologique, Oncopole Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6027-4925","authenticated-orcid":true,"given":"Olivier","family":"Sordet","sequence":"additional","affiliation":[{"name":"University of Toulouse, CNRS, INSERM, CRCT, Toulouse, France."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(11)70184-X"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14112613"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00195-8"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.84"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-024-00737-z"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.10.027"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.02.027"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4040"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49360-4"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03796-6"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.07.002"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10690"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav4474"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2018.03.004"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06303-1"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-3370"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01592-8"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.002"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2022.04.010"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.70.1.369"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.111"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-022-00452-3"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2017.06.005"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-091724-010717"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2020.102837"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2020.102900"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2014.03.020"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aax9778"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng987"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114214"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2009.11.022"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-022-00337-w"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw109"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-2246"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1039\/c1lc20128j"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.13.8516"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.192282699"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M311370200"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.631580"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2013.09.001"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2021.12.010"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2006.10.019"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1977"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2011.05.006"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1257"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.12.006"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13266"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00475a028"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/25.21.4181"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2008.06.028"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1196"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.08.041"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2009.97"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42622-7"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2796"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2015.03.003"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky694"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2017.10.003"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2016.05.011"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1406"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac073"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2004.05.008"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0708541104"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1080\/10985549.2025.2555891"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.02.036"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01047-6"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104483"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-3640"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2025.103662"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4265"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2025.116872"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201606646"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aeh9099","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:00:49Z","timestamp":1790186449000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aeh9099"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":72,"journal-issue":{"issue":"39","published-print":{"date-parts":[[2026,9,25]]}},"alternative-id":["10.1126\/sciadv.aeh9099"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aeh9099","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]},"assertion":[{"value":"2026-05-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaeh9099"}}