{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T09:29:48Z","timestamp":1787131788628,"version":"build-2736575974"},"reference-count":48,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22H03164"],"award-info":[{"award-number":["22H03164"]}],"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":["23K08142"],"award-info":[{"award-number":["23K08142"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Human Cell"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Carcinoma of unknown primary (CUP) remains a clinically challenging malignancy with limited treatment options and poor prognosis. Although genomic profiling has identified potentially actionable alterations, optimal therapeutic strategies are often unclear. Here, we report the establishment and characterization of a patient-derived tumoroid from an\n                    <jats:italic>EGFR<\/jats:italic>\n                    -amplified CUP and evaluate its utility as a functional model for therapeutic assessment. The patient-derived tumoroid (PDT-CUP#1) was successfully established from resected tumor tissue and maintained in long-term culture. Whole-exome sequencing demonstrated genomic concordance between the PDT-CUP#1 and the original tumor. Quantitative PCR and fluorescence in situ hybridization confirmed\n                    <jats:italic>EGFR<\/jats:italic>\n                    amplification. Xenograft tumors derived from PDT-CUP#1 recapitulated the histopathological features of the original lesion. Functional drug testing demonstrated differential sensitivity among EGFR-targeted agents. Whereas EGFR tyrosine kinase inhibition resulted in modest growth suppression, anti-EGFR monoclonal antibodies exhibited moderate antitumor effects, and an EGFR-targeted antibody\u2013drug conjugate showed the most pronounced growth inhibition. Notably, the therapeutic sensitivity observed in the tumoroids was generally consistent with the patient\u2019s clinical response to platinum-based chemotherapy combined with necitumumab. These findings demonstrate that a CUP-derived tumoroid can be successfully established while preserving the key molecular and pathological features of the original tumor. This model provides a platform for functional evaluation of therapeutic vulnerabilities and offers proof-of-concept for integrating patient-derived tumoroids into therapeutic decision-making in CUP.\n                  <\/jats:p>","DOI":"10.1007\/s13577-026-01440-x","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T09:21:35Z","timestamp":1787131295000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Establishment and functional characterization of an EGFR-amplified tumoroid from squamous cell carcinoma of unknown primary"],"prefix":"10.1007","volume":"39","author":[{"given":"Miki","family":"Iwai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etsuko","family":"Yokota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuro","family":"Yukawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kizuki","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Urano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazutaka","family":"Nakashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyoshi","family":"Doihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagio","family":"Takigawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyo","family":"Fujiwara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Akiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Haisa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshio","family":"Naomoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2890-0599","authenticated-orcid":false,"given":"Takuya","family":"Fukazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoki","family":"Yamatsuji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"1440_CR1","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1056\/NEJMp1500523","volume":"372","author":"FS Collins","year":"2015","unstructured":"Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372:793\u20135. https:\/\/doi.org\/10.1056\/NEJMp1500523.","journal-title":"N Engl J Med"},{"key":"1440_CR2","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1038\/s41591-023-02321-8","volume":"29","author":"V Subbiah","year":"2023","unstructured":"Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial. Nat Med. 2023;29:1103\u201312. https:\/\/doi.org\/10.1038\/s41591-023-02321-8.","journal-title":"Nat Med"},{"key":"1440_CR3","doi-asserted-by":"publisher","first-page":"1648","DOI":"10.1038\/s43018-023-00645-5","volume":"4","author":"N Liebers","year":"2023","unstructured":"Liebers N, Bruch PM, Terzer T, et al. Ex vivo drug response profiling for response and outcome prediction in hematologic malignancies: the prospective non-interventional SMARTrial. Nat Cancer. 2023;4:1648\u201359. https:\/\/doi.org\/10.1038\/s43018-023-00645-5.","journal-title":"Nat Cancer"},{"key":"1440_CR4","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/nature10868","volume":"483","author":"A Prahallad","year":"2012","unstructured":"Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483:100\u20133. https:\/\/doi.org\/10.1038\/nature10868.","journal-title":"Nature"},{"key":"1440_CR5","doi-asserted-by":"publisher","DOI":"10.3390\/bioengineering12121315","volume":"12","author":"S Motohashi","year":"2025","unstructured":"Motohashi S, Katsuta E, Ban D. Advances and challenges in drug screening for cancer therapy: a comprehensive review. Bioengineering. 2025;12:1315. https:\/\/doi.org\/10.3390\/bioengineering12121315.","journal-title":"Bioengineering"},{"key":"1440_CR6","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.ccell.2021.12.004","volume":"40","author":"A Letai","year":"2022","unstructured":"Letai A, Bhola P, Welm AL. Functional precision oncology: testing tumors with drugs to identify vulnerabilities and novel combinations. Cancer Cell. 2022;40:26\u201335. https:\/\/doi.org\/10.1016\/j.ccell.2021.12.004.","journal-title":"Cancer Cell"},{"key":"1440_CR7","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/j.trecan.2025.03.005","volume":"11","author":"SY Kim","year":"2025","unstructured":"Kim SY, van de Wetering M, Clevers H, Sanders K. The future of tumor organoids in precision therapy. Trends Cancer. 2025;11:665\u201375. https:\/\/doi.org\/10.1016\/j.trecan.2025.03.005.","journal-title":"Trends Cancer"},{"key":"1440_CR8","doi-asserted-by":"publisher","first-page":"7689","DOI":"10.1038\/s41467-025-62673-2","volume":"16","author":"F Ringnalda","year":"2025","unstructured":"Ringnalda F, van Son GJF, Verweij LHG, et al. Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibition. Nat Commun. 2025;16:7689. https:\/\/doi.org\/10.1038\/s41467-025-62673-2.","journal-title":"Nat Commun"},{"key":"1440_CR9","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-021-00166-3","volume":"5","author":"E Yokota","year":"2021","unstructured":"Yokota E, Iwai M, Yukawa T, et al. Clinical application of a lung cancer organoid (tumoroid) culture system. NPJ Precis Oncol. 2021;5:29. https:\/\/doi.org\/10.1038\/s41698-021-00166-3.","journal-title":"NPJ Precis Oncol"},{"key":"1440_CR10","doi-asserted-by":"publisher","DOI":"10.1007\/s13577-025-01206-x","volume":"38","author":"T Urano","year":"2025","unstructured":"Urano T, Yokota E, Iwai M, et al. Establishment and characterization of novel patient-derived esophageal tumoroids with long-term cultivability. Hum Cell. 2025;38:72. https:\/\/doi.org\/10.1007\/s13577-025-01206-x.","journal-title":"Hum Cell"},{"key":"1440_CR11","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.216816","volume":"588","author":"E Yokota","year":"2024","unstructured":"Yokota E, Iwai M, Yukawa T, et al. Patient-derived tumoroid models of pulmonary large-cell neuroendocrine carcinoma: a promising tool for personalized medicine and developing novel therapeutic strategies. Cancer Lett. 2024;588:216816. https:\/\/doi.org\/10.1016\/j.canlet.2024.216816.","journal-title":"Cancer Lett"},{"key":"1440_CR12","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1007\/s13577-024-01085-8","volume":"37","author":"E Yokota","year":"2024","unstructured":"Yokota E, Iwai M, Ishida Y, et al. Transforming tumoroids derived from ALK-positive pulmonary adenocarcinoma to squamous cell carcinoma in vivo. Hum Cell. 2024;37:1132\u201340. https:\/\/doi.org\/10.1007\/s13577-024-01085-8.","journal-title":"Hum Cell"},{"key":"1440_CR13","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1007\/s13577-024-01060-3","volume":"37","author":"M Iwai","year":"2024","unstructured":"Iwai M, Yokota E, Ishida Y, et al. Establishment and characterization of novel high mucus-producing lung tumoroids derived from a patient with pulmonary solid adenocarcinoma. Hum Cell. 2024;37:1194\u2013204. https:\/\/doi.org\/10.1007\/s13577-024-01060-3.","journal-title":"Hum Cell"},{"key":"1440_CR14","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1056\/NEJMra1303917","volume":"371","author":"GR Varadhachary","year":"2014","unstructured":"Varadhachary GR, Raber MN. Cancer of unknown primary site. N Engl J Med. 2014;371:757\u201365. https:\/\/doi.org\/10.1056\/NEJMra1303917.","journal-title":"N Engl J Med"},{"key":"1440_CR15","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.canep.2019.06.006","volume":"61","author":"E Rassy","year":"2019","unstructured":"Rassy E, Pavlidis N. The currently declining incidence of cancer of unknown primary. Cancer Epidemiol. 2019;61:139\u201341. https:\/\/doi.org\/10.1016\/j.canep.2019.06.006.","journal-title":"Cancer Epidemiol"},{"key":"1440_CR16","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.annonc.2022.11.013","volume":"34","author":"A Kr\u00e4mer","year":"2023","unstructured":"Kr\u00e4mer A, Bochtler T, Pauli C, et al. Cancer of unknown primary: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34:228\u201346. https:\/\/doi.org\/10.1016\/j.annonc.2022.11.013.","journal-title":"Ann Oncol"},{"key":"1440_CR17","doi-asserted-by":"publisher","first-page":"1931","DOI":"10.1001\/jamaoncol.2020.4643","volume":"6","author":"H Hayashi","year":"2020","unstructured":"Hayashi H, Takiguchi Y, Minami H, et al. Site-specific and targeted therapy based on molecular profiling by next-generation sequencing for cancer of unknown primary site: a nonrandomized phase 2 clinical trial. JAMA Oncol. 2020;6:1931\u20138. https:\/\/doi.org\/10.1001\/jamaoncol.2020.4643.","journal-title":"JAMA Oncol"},{"key":"1440_CR18","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.ejca.2019.12.016","volume":"127","author":"E Rassy","year":"2020","unstructured":"Rassy E, Bakouny Z, Choueiri TK, et al. The role of site-specific therapy for cancers of unknown of primary: a meta-analysis. Eur J Cancer. 2020;127:118\u201322. https:\/\/doi.org\/10.1016\/j.ejca.2019.12.016.","journal-title":"Eur J Cancer"},{"key":"1440_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-025-03073-7","author":"L Spurgeon","year":"2025","unstructured":"Spurgeon L, Mitchell C, Cook N, Conway AM. Cancer of unknown primary: the hunt for its elusive tissue-of-origin - is it time to call off the search? Br J Cancer. 2025. https:\/\/doi.org\/10.1038\/s41416-025-03073-7.","journal-title":"Br J Cancer"},{"key":"1440_CR20","doi-asserted-by":"publisher","DOI":"10.1038\/srep20113","volume":"6","author":"T Fukazawa","year":"2016","unstructured":"Fukazawa T, Guo M, Ishida N, et al. SOX2 suppresses CDKN1A to sustain growth of lung squamous cell carcinoma. Sci Rep. 2016;6:20113.","journal-title":"Sci Rep"},{"issue":"4","key":"1440_CR21","doi-asserted-by":"publisher","first-page":"2018100300","DOI":"10.15252\/embj.2018100300","volume":"38","author":"N Sachs","year":"2019","unstructured":"Sachs N, Papaspyropoulos A, Zomer-van Ommen DD, et al. Long term expanding human airway organoids for disease modeling. EMBO J. 2019;38(4):2018100300. https:\/\/doi.org\/10.15252\/embj.2018100300.","journal-title":"EMBO J"},{"key":"1440_CR22","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-19-1376","author":"R Shi","year":"2019","unstructured":"Shi R, Radulovich N, Ng C, et al. Organoid cultures as preclinical models of non-small cell lung cancer. Clin Cancer Res. 2019. https:\/\/doi.org\/10.1158\/1078-0432.ccr-19-1376.","journal-title":"Clin Cancer Res"},{"key":"1440_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11867-6","volume":"10","author":"M Kim","year":"2019","unstructured":"Kim M, Mun H, Sung CO, et al. Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening. Nat Commun. 2019;10:3991. https:\/\/doi.org\/10.1038\/s41467-019-11867-6.","journal-title":"Nat Commun"},{"key":"1440_CR24","doi-asserted-by":"publisher","first-page":"1936","DOI":"10.1038\/s41596-020-00474-1","volume":"16","author":"JF Dekkers","year":"2021","unstructured":"Dekkers JF, van Vliet EJ, Sachs N, et al. Long-term culture, genetic manipulation and xenotransplantation of human normal and breast cancer organoids. Nat Protoc. 2021;16:1936. https:\/\/doi.org\/10.1038\/s41596-020-00474-1.","journal-title":"Nat Protoc"},{"key":"1440_CR25","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.jcmgh.2018.09.003.eCollection19","volume":"7","author":"T Kijima","year":"2019","unstructured":"Kijima T, Nakagawa H, Shimonosono M, et al. Three-dimensional organoids reveal therapy resistance of esophageal and oropharyngeal squamous cell carcinoma cells. Cell Mol Gastroenterol Hepatol. 2019;7:73\u201391. https:\/\/doi.org\/10.1016\/j.jcmgh.2018.09.003.eCollection19.","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"1440_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05190-9","volume":"9","author":"X Li","year":"2018","unstructured":"Li X, Francies HE, Secrier M, et al. Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics. Nat Commun. 2018;9:2983. https:\/\/doi.org\/10.1038\/s41467-018-05190-9.","journal-title":"Nat Commun"},{"key":"1440_CR27","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1200\/JCO.22.01690","volume":"41","author":"VK Morris","year":"2023","unstructured":"Morris VK, Kennedy EB, Baxter NN, et al. Treatment of metastatic colorectal cancer: ASCO guideline. J Clin Oncol. 2023;41:678\u2013700. https:\/\/doi.org\/10.1200\/JCO.22.01690.","journal-title":"J Clin Oncol"},{"key":"1440_CR28","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2025.3136","author":"W Hwang","year":"2025","unstructured":"Hwang W, Ahn JS, Jung HA, Wirth LJ, Park JC. Emerging EGFR-targeted therapy in head and neck cancer: a review. JAMA Oncol. 2025. https:\/\/doi.org\/10.1001\/jamaoncol.2025.3136.","journal-title":"JAMA Oncol"},{"key":"1440_CR29","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1016\/S470-2045(15)00021-2","volume":"16","author":"N Thatcher","year":"2015","unstructured":"Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015;16:763\u201374. https:\/\/doi.org\/10.1016\/S470-2045(15)00021-2.","journal-title":"Lancet Oncol"},{"key":"1440_CR30","doi-asserted-by":"publisher","first-page":"1260419","DOI":"10.1126\/science.1260419","volume":"347","author":"M Uhl\u00e9n","year":"2015","unstructured":"Uhl\u00e9n M, Fagerberg L, Hallstr\u00f6m BM, et al. Proteomics. Tissue-based map of the human proteome. Sci. 2015;347:1260419. https:\/\/doi.org\/10.1126\/science.1260419.","journal-title":"Sci"},{"key":"1440_CR31","doi-asserted-by":"publisher","first-page":"3287","DOI":"10.1158\/078-0432.CCR-24-26","volume":"30","author":"S Jain","year":"2024","unstructured":"Jain S, Griffith JI, Porath KA, et al. Bystander effects, pharmacokinetics, and linker-payload stability of EGFR-targeting antibody-drug conjugates Losatuxizumab Vedotin and Depatux-M in glioblastoma models. Clin Cancer Res. 2024;30:3287\u201397. https:\/\/doi.org\/10.1158\/078-0432.CCR-24-26.","journal-title":"Clin Cancer Res"},{"key":"1440_CR32","first-page":"4838","volume":"57","author":"JD Moyer","year":"1997","unstructured":"Moyer JD, Barbacci EG, Iwata KK, et al. Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res. 1997;57:4838\u201348.","journal-title":"Cancer Res"},{"key":"1440_CR33","first-page":"335","volume":"1","author":"KN Ganjoo","year":"2007","unstructured":"Ganjoo KN, Wakelee H. Review of erlotinib in the treatment of advanced non-small cell lung cancer. Biologics. 2007;1:335\u201346.","journal-title":"Biologics"},{"key":"1440_CR34","doi-asserted-by":"publisher","first-page":"2035","DOI":"10.1056\/NEJMcp2402691","volume":"392","author":"K Raghav","year":"2025","unstructured":"Raghav K. Cancer of unknown primary site. N Engl J Med. 2025;392:2035\u201347. https:\/\/doi.org\/10.1056\/NEJMcp2402691.","journal-title":"N Engl J Med"},{"key":"1440_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22643-w","volume":"12","author":"F Verginelli","year":"2021","unstructured":"Verginelli F, Pisacane A, Gambardella G, et al. Cancer of unknown primary stem-like cells model multi-organ metastasis and unveil liability to MEK inhibition. Nat Commun. 2021;12:2498. https:\/\/doi.org\/10.1038\/s41467-021-22643-w.","journal-title":"Nat Commun"},{"key":"1440_CR36","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1159\/000538137","volume":"17","author":"L Ruhe","year":"2024","unstructured":"Ruhe L, Heibl S, Czompo M, et al. Functional precision medicine successfully guides therapeutic regimen of \u2018cancer of unknown primary\u2019 later classified as triple-negative breast cancer: a case report. Case Rep Oncol. 2024;17:490\u20136. https:\/\/doi.org\/10.1159\/000538137.","journal-title":"Case Rep Oncol"},{"key":"1440_CR37","doi-asserted-by":"publisher","first-page":"3650","DOI":"10.1016\/j.ymthe.2024.07.011","volume":"32","author":"A Cavazzoni","year":"2024","unstructured":"Cavazzoni A, Salamon I, Fumarola C, et al. Synergic activity of FGFR2 and MEK inhibitors in the treatment of FGFR2-amplified cancers of unknown primary. Mol Ther. 2024;32:3650\u201368. https:\/\/doi.org\/10.1016\/j.ymthe.2024.07.011.","journal-title":"Mol Ther"},{"key":"1440_CR38","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1016\/j.jmoldx.2020.06.005","volume":"22","author":"Q Ye","year":"2020","unstructured":"Ye Q, Wang Q, Qi P, et al. Development and clinical validation of a 90-gene expression assay for identifying tumor tissue origin. J Mol Diagn. 2020;22:1139\u201350. https:\/\/doi.org\/10.1016\/j.jmoldx.2020.06.005.","journal-title":"J Mol Diagn"},{"key":"1440_CR39","doi-asserted-by":"publisher","first-page":"722808","DOI":"10.3389\/fonc.2021.722808.eCollection2021","volume":"11","author":"Y Zhang","year":"2021","unstructured":"Zhang Y, Xia L, Ma D, Wu J, Xu X, Xu Y. 90-gene expression profiling for tissue origin diagnosis of cancer of unknown primary. Front Oncol. 2021;11:722808. https:\/\/doi.org\/10.3389\/fonc.2021.722808.eCollection2021.","journal-title":"Front Oncol"},{"key":"1440_CR40","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1186\/s12885-020-07640-4","volume":"20","author":"Y Mitani","year":"2020","unstructured":"Mitani Y, Kanai M, Kou T, et al. Cancer of unknown primary with EGFR mutation successfully treated with targeted therapy directed by clinical next-generation sequencing: a case report. BMC Cancer. 2020;20:1177. https:\/\/doi.org\/10.1186\/s12885-020-07640-4.","journal-title":"BMC Cancer"},{"key":"1440_CR41","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000032615","volume":"102","author":"HJ Du","year":"2023","unstructured":"Du HJ, Chen FF, Liu Y, Zhou Y. Bone metastatic carcinoma with EGFR amplification and mutation: a case report and literature review. Med (Baltimore). 2023;102:e32615. https:\/\/doi.org\/10.1097\/MD.0000000000032615.","journal-title":"Med (Baltimore)"},{"key":"1440_CR42","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1056\/NEJMoa040938","volume":"350","author":"TJ Lynch","year":"2004","unstructured":"Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129\u201339. https:\/\/doi.org\/10.1056\/NEJMoa040938.","journal-title":"N Engl J Med"},{"key":"1440_CR43","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.ccr.2005.03.003","volume":"7","author":"S Li","year":"2005","unstructured":"Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, Ferguson KM. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell. 2005;7:301\u201311. https:\/\/doi.org\/10.1016\/j.ccr.2005.03.003.","journal-title":"Cancer Cell"},{"key":"1440_CR44","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1016\/S470-2045(15)70046-X","volume":"16","author":"L Paz-Ares","year":"2015","unstructured":"Paz-Ares L, Mezger J, Ciuleanu TE, et al. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study. Lancet Oncol. 2015;16:328\u201337. https:\/\/doi.org\/10.1016\/S470-2045(15)70046-X.","journal-title":"Lancet Oncol"},{"key":"1440_CR45","doi-asserted-by":"publisher","first-page":"6770","DOI":"10.1158\/0008-5472.CAN-13-1145","volume":"73","author":"J Cho","year":"2013","unstructured":"Cho J, Chen L, Sangji N, et al. Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization. Cancer Res. 2013;73:6770\u20139. https:\/\/doi.org\/10.1158\/0008-5472.CAN-13-1145.","journal-title":"Cancer Res"},{"key":"1440_CR46","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1158\/1535-7163.MCT-19-0609","volume":"19","author":"C von Achenbach","year":"2020","unstructured":"von Achenbach C, Silginer M, Blot V, Weiss WA, Weller M. Depatuxizumab Mafodotin (ABT-414)-induced Glioblastoma cell death requires EGFR overexpression, but not EGFR(Y1068) phosphorylation. Mol Cancer Ther. 2020;19:1328\u201339. https:\/\/doi.org\/10.1158\/1535-7163.MCT-19-0609.","journal-title":"Mol Cancer Ther"},{"key":"1440_CR47","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1093\/neuonc\/noz222","volume":"22","author":"M Van Den Bent","year":"2020","unstructured":"Van Den Bent M, Eoli M, Sepulveda JM, et al. INTELLANCE 2\/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFR amplified glioblastoma. Neuro Oncol. 2020;22:684\u201393. https:\/\/doi.org\/10.1093\/neuonc\/noz222.","journal-title":"Neuro Oncol"},{"key":"1440_CR48","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.cell.2018.07.042","volume":"175","author":"KA Knouse","year":"2018","unstructured":"Knouse KA, Lopez KE, Bachofner M, Amon A. Chromosome segregation fidelity in epithelia requires tissue architecture. Cell. 2018;175:200-11.e13. https:\/\/doi.org\/10.1016\/j.cell.2018.07.042.","journal-title":"Cell"}],"container-title":["Human Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13577-026-01440-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s13577-026-01440-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13577-026-01440-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T09:21:36Z","timestamp":1787131296000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s13577-026-01440-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":48,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["1440"],"URL":"https:\/\/doi.org\/10.1007\/s13577-026-01440-x","relation":{},"ISSN":["1749-0774"],"issn-type":[{"value":"1749-0774","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]},"assertion":[{"value":"23 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Hiroyoshi Doihara reports receiving honoraria from Eli Lilly Japan (Japan). Nagio Takigawa reports receiving grants and honoraria from Eli Lilly Japan and Nippon Kayaku (Japan).","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Approval of the research protocol by an Institutional Review Board: The research protocol was approved by the Ethics Committee of Kawasaki Medical School (approval no. 3171-8).","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Animal studies: All animal studies were approved by the Animal Research Committee of Kawasaki Medical School (approval no. 25-029).","order":3,"name":"Ethics","label":"Human and animal rights statements","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The patient who participated in the present study signed an informed consent form approved by the responsible authority.Written informed consent was obtained from all the patients per the study protocol.","order":4,"name":"Ethics","label":"Informed consent","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"127"}}