{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T12:24:12Z","timestamp":1788265452384,"version":"build-2803163510"},"reference-count":37,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP19K08625"],"award-info":[{"award-number":["JP19K08625"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP22K19529"],"award-info":[{"award-number":["JP22K19529"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP23K24339"],"award-info":[{"award-number":["JP23K24339"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24K02333"],"award-info":[{"award-number":["JP24K02333"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24K02459"],"award-info":[{"award-number":["JP24K02459"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP26K02424"],"award-info":[{"award-number":["JP26K02424"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007412","name":"Nippon Foundation","doi-asserted-by":"publisher","award":["2026001344"],"award-info":[{"award-number":["2026001344"]}],"id":[{"id":"10.13039\/501100007412","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001003","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001003","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP25ama221242h0001"],"award-info":[{"award-number":["JP25ama221242h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP25ck0106795h0003"],"award-info":[{"award-number":["JP25ck0106795h0003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP26ama221242h0002"],"award-info":[{"award-number":["JP26ama221242h0002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Osimertinib is the standard first\u2010line treatment for advanced\n                    <jats:italic>EGFR<\/jats:italic>\n                    \u2010mutant non\u2010small cell lung cancer. However, acquired resistance invariably develops, and identifying novel resistance pathways is clinically important as a substantial portion remains undefined. We used an immunocompetent syngeneic lung cancer mouse model harboring an\n                    <jats:italic>Egfr<\/jats:italic>\n                    exon 19 deletion (mDEL tumors) to establish acquired resistance. Osimertinib\u2010resistant tumors were generated in\u00a0vivo using a drug\u2010holiday\/re\u2010challenge protocol. The resistance mechanism was identified using Sanger sequencing, receptor tyrosine kinase arrays, and western blotting.\n                    <jats:italic>Egfr<\/jats:italic>\n                    V804F knock\u2010in cells were generated using CRISPR\/Cas9, and their sensitivity to osimertinib and afatinib was assessed in\u00a0vitro and in\u00a0vivo. We established two distinct osimertinib\u2010resistant tumor lines in a syngeneic lung cancer mouse model (mDEL OsiR #1\/#3). The analysis revealed an on\u2010target secondary\n                    <jats:italic>Egfr<\/jats:italic>\n                    V804F mutation (corresponding to human\n                    <jats:italic>EGFR<\/jats:italic>\n                    V802F) in both tumor lines. Importantly,\n                    <jats:italic>Egfr<\/jats:italic>\n                    V804F knock\u2010in cells demonstrated significant osimertinib resistance, with a 5.7\u201310.5\u2010fold increase in in\u00a0vitro IC\n                    <jats:sub>50<\/jats:sub>\n                    (mean, 8.2\u2010fold), but remained highly sensitive to afatinib. Furthermore, afatinib effectively overcame osimertinib resistance in the V804F knock\u2010in cell\u2010derived mouse model. Consistently, afatinib treatment resulted in marked tumor shrinkage and suppression of EGFR signaling in the established mDEL OsiR #1\/#3 in\u00a0vivo. These findings establish secondary\n                    <jats:italic>Egfr<\/jats:italic>\n                    V804F\/\n                    <jats:italic>EGFR<\/jats:italic>\n                    V802F as an on\u2010target osimertinib resistance mechanism, providing a preclinical rationale for evaluating afatinib in biomarker\u2010selected patients harboring this alteration.\n                  <\/jats:p>","DOI":"10.1111\/cas.70431","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:56:16Z","timestamp":1780379776000},"page":"2426-2442","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Afatinib Overcomes Osimertinib Resistance via\n                    <i>Egfr<\/i>\n                    <scp>V804F<\/scp>\n                    Mutation in a Syngeneic\n                    <i>Egfr<\/i>\n                    \u2010Mutant Lung Cancer Mouse Model"],"prefix":"10.1111","volume":"117","author":[{"given":"Takaaki","family":"Tanaka","sequence":"first","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Fujitani","sequence":"additional","affiliation":[{"name":"Division of Experimental Chemotherapy, Cancer Chemotherapy Center Japanese Foundation for Cancer Research  Tokyo Japan"},{"name":"Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Taoka","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwao","family":"Shimomura","sequence":"additional","affiliation":[{"name":"Division of Experimental Chemotherapy, Cancer Chemotherapy Center Japanese Foundation for Cancer Research  Tokyo Japan"},{"name":"Department of Respirology, Graduate School of Medicine Chiba University  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachi","family":"Okawa","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunta","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadahiro","family":"Kuribayashi","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoka","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naofumi","family":"Hara","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiichiro","family":"Ninomiya","sequence":"additional","affiliation":[{"name":"Center for Comprehensive Genomic Medicine Okayama University Hospital  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Go","family":"Makimoto","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisao","family":"Higo","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kammei","family":"Rai","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2966-106X","authenticated-orcid":false,"given":"Eiki","family":"Ichihara","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3786-936X","authenticated-orcid":false,"given":"Shuta","family":"Tomida","sequence":"additional","affiliation":[{"name":"Center for Comprehensive Genomic Medicine Okayama University Hospital  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0112-0843","authenticated-orcid":false,"given":"Katsuyuki","family":"Hotta","sequence":"additional","affiliation":[{"name":"Center for Innovative Clinical Medicine Okayama University Hospital  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9910-0164","authenticated-orcid":false,"given":"Yosuke","family":"Togashi","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinobu","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuyuki","family":"Kiura","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7394-895X","authenticated-orcid":false,"given":"Ryohei","family":"Katayama","sequence":"additional","affiliation":[{"name":"Division of Experimental Chemotherapy, Cancer Chemotherapy Center Japanese Foundation for Cancer Research  Tokyo Japan"},{"name":"Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5180-3933","authenticated-orcid":false,"given":"Kadoaki","family":"Ohashi","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0802714"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010023\u201000844\u20100"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/dji055"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.43.3912"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1713137"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1913662"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201035961\u2010y"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201035962\u2010x"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.01585"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201019\u20103563"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201014\u20103167"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201017\u20101574"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349\u20107006.2008.00875.x"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2019.08.019"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.003681"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432\u2010008\u20100512\u20101"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2017.04.003"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201017\u20102310"},{"issue":"11","key":"e_1_2_14_20_1","first-page":"4005","article-title":"Acquired Rare Recurrent EGFR Mutations as Mechanisms of Resistance to Osimertinib in Lung Cancer and in Silico Structural Modelling","volume":"10","author":"Lin L.","year":"2020","journal-title":"American Journal of Cancer Research"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2024.14827"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2503001"},{"key":"e_1_2_14_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2510308"},{"key":"e_1_2_14_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2024.12.027"},{"key":"e_1_2_14_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2023.107426"},{"key":"e_1_2_14_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctarc.2026.101105"},{"key":"e_1_2_14_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2025.04.003"},{"key":"e_1_2_14_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388\u2010022\u201002263\u20104"},{"key":"e_1_2_14_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2023.09.1453"},{"key":"e_1_2_14_30_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1609907"},{"key":"e_1_2_14_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.02.027"},{"key":"e_1_2_14_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4040"},{"key":"e_1_2_14_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3388"},{"key":"e_1_2_14_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2016.05.010"},{"key":"e_1_2_14_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003898\u20101"},{"key":"e_1_2_14_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2024.107988"},{"key":"e_1_2_14_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctarc.2021.100497"},{"key":"e_1_2_14_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtocrr.2021.100193"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.70431","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cas.70431","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.70431","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T12:02:09Z","timestamp":1788264129000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.70431"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,1]]},"references-count":37,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1111\/cas.70431"],"URL":"https:\/\/doi.org\/10.1111\/cas.70431","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,1]]},"assertion":[{"value":"2025-12-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}