{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T10:10:02Z","timestamp":1778148602099,"version":"3.51.4"},"reference-count":88,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["A24881"],"award-info":[{"award-number":["A24881"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["17\/18_MSD_1102839"],"award-info":[{"award-number":["17\/18_MSD_1102839"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MRC295X"],"award-info":[{"award-number":["MRC295X"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000771","name":"Prostate Cancer UK","doi-asserted-by":"publisher","award":["RIA_ST2_024"],"award-info":[{"award-number":["RIA_ST2_024"]}],"id":[{"id":"10.13039\/501100000771","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"abstract":"<jats:p>The insulin\u2010like growth factor (IGF) axis regulates cancer cell proliferation, growth, invasion, and therapy resistance. Elevated expression of the type 1 IGF receptor (IGF\u20101R) is linked to radioresistance and biochemical recurrence in prostate cancer, yet the molecular mechanisms underlying IGF\u20101R\u2013mediated DNA damage responses remain unclear. We investigated the role of IGF\u20101R in DNA double\u2010strand break (DSB) repair by assessing chromatin recruitment of DNA repair proteins, repair pathway usage, and therapeutic sensitivity in cancer cell models with altered IGF\u20101R status. Loss of IGF\u20101R impaired DNA\u2010dependent protein kinase catalytic subunit (DNA\u2010PKcs) localisation to chromatin, resulting in defective non\u2010homologous end\u2010joining (NHEJ) and a compensatory reliance on alternative repair pathways, including microhomology\u2010mediated end\u2010joining (MMEJ). Modulating IGF\u20101R expression restored radiosensitivity in poly (ADP\u2010ribose) polymerase (PARP) inhibitor\u2013resistant breast cancer cells. IGF\u20101R inhibition compromises canonical DSB repair and re\u2010sensitises resistant cancer cells to therapy, supporting its potential as a therapeutic strategy in homologous recombination\u2013deficient tumours. Furthermore, IGF\u20101R mutant cancers may benefit from targeted inhibition of the MMEJ pathway.<\/jats:p>","DOI":"10.1002\/1878-0261.70266","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T09:09:57Z","timestamp":1778144997000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Loss of\n                    <scp>IGF<\/scp>\n                    \u2010\n                    <scp>1R<\/scp>\n                    impairs\n                    <scp>DNA<\/scp>\n                    \u2010\n                    <scp>PKcs<\/scp>\n                    recruitment to chromatin leading to defective end\u2010joining"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4541-3967","authenticated-orcid":false,"given":"Matthew O.","family":"Ellis","sequence":"first","affiliation":[{"name":"UK\u2010DRI, Department of Clinical Neuroscience University of Cambridge  Cambridge England"},{"name":"Nuffield Department of Surgical Sciences University of Oxford  Oxford England"},{"name":"Institute of Cancer Research  London England"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack V.","family":"Mills","sequence":"additional","affiliation":[{"name":"Nuffield Department of Surgical Sciences University of Oxford  Oxford England"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8518-6304","authenticated-orcid":false,"given":"Wojciech","family":"Niedzwiedz","sequence":"additional","affiliation":[{"name":"Institute of Cancer Research  London England"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentine M.","family":"Macaulay","sequence":"additional","affiliation":[{"name":"Nuffield Department of Surgical Sciences University of Oxford  Oxford England"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.g1502"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2214122"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1606220"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(19)31131\u20106"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bju.14987"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1615\/CritRevOncog.2018025946"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11523\u2010017\u20100514\u20105"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201007\u20104879"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2017.337"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/238757"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14205032"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2024.100499"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2012.03.009"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.460"},{"key":"e_1_2_11_16_1","first-page":"3079","article-title":"Insulin\u2010like growth factor\u2010I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation","volume":"57","author":"Turner B","year":"1997","journal-title":"Cancer Res"},{"issue":"35","key":"e_1_2_11_17_1","doi-asserted-by":"crossref","first-page":"56826","DOI":"10.18632\/oncotarget.10862","article-title":"IGF\u20101R inhibition sensitizes breast cancer cells to ATM\u2010related kinase (ATR) inhibitor and cisplatin","volume":"7","author":"O'Flanagan CH","year":"2016","journal-title":"Oncotarget"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2004.10.002"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2010.10.003"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/5497467"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416\u2010019\u20100677\u20101"},{"issue":"10","key":"e_1_2_11_22_1","first-page":"3206","article-title":"Antiapoptotic activity is dispensable for insulin\u2010like growth factor I receptor\u2010mediated Clonogenic Radioresistance after \u03b3\u2010Irradiation1","volume":"7","author":"Tezuka M","year":"2001","journal-title":"Clin Cancer Res"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201003917\u20102"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.MCT\u201013\u20100598"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416\u2010020\u20100774\u20101"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201020\u20102860"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201303073"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1261971"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/1521\u20104141(200203)32:3<701::AID\u2010IMMU701>3.0.CO;2\u2010T"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2011.240"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11626\u2010999\u20100115\u20104"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1677\/ERC\u201008\u20100084"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201005\u20102925"},{"issue":"18","key":"e_1_2_11_34_1","first-page":"4848","article-title":"Growth inhibition of human melanoma cells in nude mice by antisense strategies to the type 1 insulin\u2010like growth factor Receptor1","volume":"54","author":"Resnicoff M","year":"1994","journal-title":"Cancer Res"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.9.4.10764"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.6.5.3901"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2004.10.029"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2017.06.011"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/jrr\/rraa053"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.3791\/56617"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.05.015"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1446"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2017"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.MCT\u201007\u20102200"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541\u20107786.MCR\u201011\u20100592"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201008\u20100861"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18112473"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20246316"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.104372"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201008\u20103009"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406731200"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.107.044743"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410344200"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201021\u20101846"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2000628"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201010\u20100052"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201017\u20103498"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.781492"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.165"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2019.01.002"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/27.17.3494"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.5.3267"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e16\u201008\u20100573"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.03.058"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010019\u201012836\u20109"},{"issue":"8","key":"e_1_2_11_66_1","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1101\/gad.13.8.916","article-title":"The DNA\u2010dependent protein kinase","volume":"13","author":"Smith GCM","year":"1999","journal-title":"Genes Dev"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1202"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2015.08.006"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.48"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.TM117.000375"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv894"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.26201"},{"key":"e_1_2_11_73_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes10040284"},{"key":"e_1_2_11_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2018.08.022"},{"key":"e_1_2_11_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03445"},{"key":"e_1_2_11_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03443"},{"key":"e_1_2_11_77_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010020\u201001227\u20100"},{"key":"e_1_2_11_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2018.08.021"},{"key":"e_1_2_11_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010021\u201000532\u2010x"},{"key":"e_1_2_11_80_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2019.07.008"},{"key":"e_1_2_11_81_1","doi-asserted-by":"publisher","DOI":"10.3892\/or.2021.8119"},{"key":"e_1_2_11_82_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41698\u2010024\u201000655\u20101"},{"key":"e_1_2_11_83_1","doi-asserted-by":"publisher","DOI":"10.14348\/molcells.2023.2164"},{"key":"e_1_2_11_84_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201049316\u20108"},{"key":"e_1_2_11_85_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201022\u20101124"},{"key":"e_1_2_11_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2015.09.009"},{"key":"e_1_2_11_87_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885\u2010015\u20101803\u2010y"},{"key":"e_1_2_11_88_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000855"},{"key":"e_1_2_11_89_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1209"}],"container-title":["Molecular Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.70266","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/1878-0261.70266","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.70266","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T09:09:59Z","timestamp":1778144999000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1002\/1878-0261.70266"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,7]]},"references-count":88,"alternative-id":["10.1002\/1878-0261.70266"],"URL":"https:\/\/doi.org\/10.1002\/1878-0261.70266","archive":["Portico"],"relation":{},"ISSN":["1574-7891","1878-0261"],"issn-type":[{"value":"1574-7891","type":"print"},{"value":"1878-0261","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,7]]},"assertion":[{"value":"2025-10-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"1878-0261.70266"}}