{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:26:30Z","timestamp":1787005590645,"version":"build-2736575974"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"34","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Oncogene"],"published-print":{"date-parts":[[2026,9,8]]},"DOI":"10.1038\/s41388-026-03907-5","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T16:35:25Z","timestamp":1784824525000},"page":"3586-3603","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Activation of the NF-\u03baB\/ALDH1A1 signaling promotes non-mutational resistance to EGFR-TKIs in non-small cell lung cancer"],"prefix":"10.1038","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3847-2807","authenticated-orcid":false,"given":"Lingyu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4427-8399","authenticated-orcid":false,"given":"Guibin","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9157-274X","authenticated-orcid":false,"given":"Chunjiang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3422-0631","authenticated-orcid":false,"given":"Ruoxin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5089-0131","authenticated-orcid":false,"given":"Yang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3230-631X","authenticated-orcid":false,"given":"Chuanzhong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wansong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2345-4040","authenticated-orcid":false,"given":"Dali","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0256-987X","authenticated-orcid":false,"given":"Yunbin","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"3907_CR1","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1200\/JCO.2010.32.6181","volume":"29","author":"SP D\u2019Angelo","year":"2011","unstructured":"D\u2019Angelo SP, Pietanza MC, Johnson ML, Riely GJ, Miller VA, Sima CS, et al. Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol. 2011;29:2066\u201370.","journal-title":"J Clin Oncol"},{"key":"3907_CR2","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/nrc2088","volume":"7","author":"SV Sharma","year":"2007","unstructured":"Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7:169\u201381.","journal-title":"Nat Rev Cancer"},{"key":"3907_CR3","doi-asserted-by":"publisher","DOI":"10.1136\/esmoopen-2016-000060","volume":"1","author":"F Morgillo","year":"2016","unstructured":"Morgillo F, Della Corte CM, Fasano M, Ciardiello F. Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO Open. 2016;1:e000060.","journal-title":"ESMO Open"},{"key":"3907_CR4","doi-asserted-by":"publisher","first-page":"2070","DOI":"10.1073\/pnas.0709662105","volume":"105","author":"CH Yun","year":"2008","unstructured":"Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong K, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA. 2008;105:2070\u20135.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3907_CR5","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/nrclinonc.2014.104","volume":"11","author":"DR Camidge","year":"2014","unstructured":"Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014;11:473\u201381.","journal-title":"Nat Rev Clin Oncol"},{"key":"3907_CR6","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1016\/j.trecan.2016.05.010","volume":"2","author":"JJ Lin","year":"2016","unstructured":"Lin JJ, Shaw AT. Resisting Resistance: Targeted Therapies in Lung Cancer. Trends Cancer. 2016;2:350\u201364.","journal-title":"Trends Cancer"},{"key":"3907_CR7","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0777-1","volume":"17","author":"SG Wu","year":"2018","unstructured":"Wu SG, Shih JY. Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer. Mol Cancer. 2018;17:38.","journal-title":"Mol Cancer"},{"key":"3907_CR8","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1016\/j.stem.2024.06.003","volume":"31","author":"PE Saw","year":"2024","unstructured":"Saw PE, Liu Q, Wong PP, Song E. Cancer stem cell mimicry for immune evasion and therapeutic resistance. Cell Stem Cell. 2024;31:1101\u201312.","journal-title":"Cell Stem Cell"},{"key":"3907_CR9","doi-asserted-by":"publisher","first-page":"1621","DOI":"10.1016\/j.ccell.2023.07.012","volume":"41","author":"Q Huang","year":"2023","unstructured":"Huang Q, Liu L, Xiao D, Huang Z, Wang W, Zhai K, et al. CD44+ lung cancer stem cell-derived pericyte-like cells cause brain metastases through GPR124-enhanced trans-endothelial migration. Cancer Cell. 2023;41:1621\u20131636.e8.","journal-title":"Cancer Cell"},{"key":"3907_CR10","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.canlet.2016.01.012","volume":"372","author":"L MacDonagh","year":"2016","unstructured":"MacDonagh L, Gray SG, Breen E, Cuffe S, Finn SP, O\u2019Byrne KJ, et al. Lung cancer stem cells: The root of resistance. Cancer Lett. 2016;372:147\u201356.","journal-title":"Cancer Lett"},{"key":"3907_CR11","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1158\/1541-7786.MCR-08-0393","volume":"7","author":"F Jiang","year":"2009","unstructured":"Jiang F, Qiu Q, Khanna A, Todd NW, Deepak J, Xing L, et al. Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res. 2009;7:330\u20138.","journal-title":"Mol Cancer Res"},{"key":"3907_CR12","first-page":"16","volume":"5","author":"J Codony-Servat","year":"2016","unstructured":"Codony-Servat J, Verlicchi A, Rosell R. Cancer stem cells in small cell lung cancer. Transl Lung Cancer Res. 2016;5:16\u201325.","journal-title":"Transl Lung Cancer Res"},{"key":"3907_CR13","first-page":"a041270","volume":"12","author":"SP Rowbotham","year":"2022","unstructured":"Rowbotham SP, Goruganthu MUL, Arasada RR, Wang WZ, Carbone DP, Kim CF. Lung Cancer Stem Cells and Their Clinical Implications. Cold Spring Harb Perspect Med. 2022;12:a041270.","journal-title":"Cold Spring Harb Perspect Med"},{"key":"3907_CR14","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.stem.2018.11.017","volume":"24","author":"C Saygin","year":"2019","unstructured":"Saygin C, Matei D, Majeti R, Reizes O, Lathia JD. Targeting Cancer Stemness in the Clinic: From Hype to Hope. Cell Stem Cell. 2019;24:25\u201340.","journal-title":"Cell Stem Cell"},{"key":"3907_CR15","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202200364","volume":"18","author":"Y Zhang","year":"2022","unstructured":"Zhang Y, Wang Z, Hu Q, Luo H, Lu B, Gao Y, et al. 3D Bioprinted GelMA-Nanoclay Hydrogels Induce Colorectal Cancer Stem Cells Through Activating Wnt\/\u03b2-Catenin Signaling. Small. 2022;18:e2200364.","journal-title":"Small"},{"key":"3907_CR16","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1038\/nature07935","volume":"459","author":"T Sato","year":"2009","unstructured":"Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459:262\u20135.","journal-title":"Nature"},{"key":"3907_CR17","doi-asserted-by":"publisher","DOI":"10.1126\/science.1247125","volume":"345","author":"MA Lancaster","year":"2014","unstructured":"Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science. 2014;345:1247125.","journal-title":"Science"},{"key":"3907_CR18","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1158\/1078-0432.CCR-19-1376","volume":"26","author":"R Shi","year":"2020","unstructured":"Shi R, Radulovich N, Ng C, Liu N, Notsuda H, Cabanero M, et al. Organoid Cultures as Preclinical Models of Non-Small Cell Lung Cancer. Clin Cancer Res. 2020;26:1162\u201374.","journal-title":"Clin Cancer Res"},{"key":"3907_CR19","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.ccell.2024.01.012","volume":"42","author":"X Tong","year":"2024","unstructured":"Tong X, Patel AS, Kim E, Li H, Chen Y, Li S, et al. Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer. Cancer Cell. 2024;42:413\u2013428.e7.","journal-title":"Cancer Cell"},{"key":"3907_CR20","doi-asserted-by":"publisher","first-page":"7265","DOI":"10.1038\/s41388-020-01492-9","volume":"39","author":"S Ukai","year":"2020","unstructured":"Ukai S, Honma R, Sakamoto N, Yamamoto Y, Pham QT, Harada K, et al. Molecular biological analysis of 5-FU-resistant gastric cancer organoids; KHDHRBS3 contributes to the attainment of features of cancer stem cell. Oncogene. 2020;39:7265\u201378.","journal-title":"Oncogene"},{"key":"3907_CR21","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1038\/nm.4040","volume":"22","author":"AN Hata","year":"2016","unstructured":"Hata AN, Niederst MJ, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Mulvey HE, et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med. 2016;22:262\u20139.","journal-title":"Nat Med"},{"key":"3907_CR22","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","volume":"26","author":"H Li","year":"2010","unstructured":"Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26:589\u201395.","journal-title":"Bioinformatics"},{"key":"3907_CR23","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/nbt.2514","volume":"31","author":"K Cibulskis","year":"2013","unstructured":"Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31:213\u20139.","journal-title":"Nat Biotechnol"},{"key":"3907_CR24","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","volume":"38","author":"K Wang","year":"2010","unstructured":"Wang K, Li M, Hakonarson H. ANNOVAR: from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.","journal-title":"Nucleic Acids Res"},{"key":"3907_CR25","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1093\/bioinformatics\/btr670","volume":"28","author":"V Boeva","year":"2012","unstructured":"Boeva V, Popova T, Bleakley K, Chiche P, Cappo J, Schleiermacher G, et al. Control-FREEC: a tool for assessing copy number and allelic content using next-generation sequencing data. Bioinformatics. 2012;28:423\u20135.","journal-title":"Bioinformatics"},{"key":"3907_CR26","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, Rosenbluth JM, Kopper O, Rebel HG, et al. Long-term culture, genetic manipulation and xenotransplantation of human normal and breast cancer organoids. Nat Protoc. 2021;16:1936\u201365.","journal-title":"Nat Protoc"},{"key":"3907_CR27","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/360438","volume":"2014","author":"A Ayala","year":"2014","unstructured":"Ayala A, Mu\u00f1oz MF, Arg\u00fcelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxynonenal. Oxid Med Cell Longev. 2014;2014:360438.","journal-title":"Oxid Med Cell Longev"},{"key":"3907_CR28","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.canlet.2021.08.009","volume":"520","author":"H Yi","year":"2021","unstructured":"Yi H, Liang L, Wang H, Luo S, Hu L, Wang Y, et al. Albendazole inhibits NF-\u03baB signaling pathway to overcome tumor stemness and bortezomib resistance in multiple myeloma. Cancer Lett. 2021;520:307\u201320.","journal-title":"Cancer Lett"},{"key":"3907_CR29","first-page":"115","volume":"3","author":"BG Campling","year":"1997","unstructured":"Campling BG, Young LC, Baer KA, Lam YM, Deeley RG, Cole SP, et al. Expression of the MRP and MDR1 multidrug resistance genes in small cell lung cancer. Clin Cancer Res. 1997;3:115\u201322.","journal-title":"Clin Cancer Res"},{"key":"3907_CR30","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1186\/s13046-019-1486-3","volume":"38","author":"J Si","year":"2019","unstructured":"Si J, Ma Y, Bi JW, Xiong Y, Lv C, Li S, et al. Shisa3 brakes resistance to EGFR-TKIs in lung adenocarcinoma by suppressing cancer stem cell properties. J Exp Clin Cancer Res. 2019;38:481.","journal-title":"J Exp Clin Cancer Res"},{"key":"3907_CR31","doi-asserted-by":"publisher","first-page":"2433","DOI":"10.1158\/1535-7163.MCT-15-0050","volume":"14","author":"T Sugano","year":"2015","unstructured":"Sugano T, Seike M, Noro R, Soeno C, Chiba M, Zou F, et al. Inhibition of ABCB1 Overcomes Cancer Stem Cell-like Properties and Acquired Resistance to MET Inhibitors in Non-Small Cell Lung Cancer. Mol Cancer Ther. 2015;14:2433\u201340.","journal-title":"Mol Cancer Ther"},{"key":"3907_CR32","doi-asserted-by":"publisher","first-page":"5919","DOI":"10.1158\/0008-5472.CAN-21-1337","volume":"81","author":"C Liu","year":"2021","unstructured":"Liu C, Qiang J, Deng Q, Xia J, Deng L, Zhou L, et al. ALDH1A1 Activity in Tumor-Initiating Cells Remodels Myeloid-Derived Suppressor Cells to Promote Breast Cancer Progression. Cancer Res. 2021;81:5919\u201334.","journal-title":"Cancer Res"},{"key":"3907_CR33","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/0092-8674(87)90362-X","volume":"48","author":"ML Atchison","year":"1987","unstructured":"Atchison ML, Perry RP. The role of the kappa enhancer and its binding factor NF-kappa B in the developmental regulation of kappa gene transcription. Cell. 1987;48:121\u20138.","journal-title":"Cell"},{"key":"3907_CR34","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1038\/nrc3204","volume":"12","author":"ND Perkins","year":"2012","unstructured":"Perkins ND. The diverse and complex roles of NF-\u03baB subunits in cancer. Nat Rev Cancer. 2012;12:121\u201332.","journal-title":"Nat Rev Cancer"},{"key":"3907_CR35","doi-asserted-by":"publisher","first-page":"4417","DOI":"10.2147\/IJN.S243657","volume":"15","author":"L Zhang","year":"2020","unstructured":"Zhang L, Chen W, Tu G, Chen X, Lu Y, Wu L, et al. Enhanced Chemotherapeutic Efficacy of PLGA-Encapsulated Epigallocatechin Gallate (EGCG) Against Human Lung Cancer. Int J Nanomedicine. 2020;15:4417\u201329.","journal-title":"Int J Nanomedicine"},{"key":"3907_CR36","doi-asserted-by":"publisher","first-page":"6543","DOI":"10.7150\/jca.34285","volume":"10","author":"L Zhang","year":"2019","unstructured":"Zhang L, Xie J, Gan R, Wu Z, Luo H, Chen X, et al. Synergistic inhibition of lung cancer cells by EGCG and NF-\u03baB inhibitor BAY11-7082. J Cancer. 2019;10:6543\u201356.","journal-title":"J Cancer"},{"key":"3907_CR37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114900","volume":"245","author":"L Xu","year":"2023","unstructured":"Xu L, Xu B, Wang J, Gao Y, He X, Xie T, et al. Recent advances of novel fourth generation EGFR inhibitors in overcoming C797S mutation of lung cancer therapy. Eur J Med Chem. 2023;245:114900.","journal-title":"Eur J Med Chem"},{"key":"3907_CR38","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.lungcan.2016.05.015","volume":"98","author":"SI Ou","year":"2016","unstructured":"Ou SI, Agarwal N, Ali SM. High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression. Lung Cancer. 2016;98:59\u201361.","journal-title":"Lung Cancer"},{"key":"3907_CR39","doi-asserted-by":"publisher","DOI":"10.1177\/17588359221144099","volume":"14","author":"J Lee","year":"2022","unstructured":"Lee J, Piotrowska Z, Soo R, Cho BC, Lim SM. Combatting acquired resistance to osimertinib in EGFR-mutant lung cancer. Ther Adv Med Oncol. 2022;14:17588359221144099.","journal-title":"Ther Adv Med Oncol"},{"key":"3907_CR40","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1200\/JCO.18.01585","volume":"37","author":"N Marcoux","year":"2019","unstructured":"Marcoux N, Gettinger SN, O\u2019Kane G, Arbour KC, Neal JW, Husain H, et al. EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes. J Clin Oncol. 2019;37:278\u201385.","journal-title":"J Clin Oncol"},{"key":"3907_CR41","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.cell.2008.01.020","volume":"132","author":"MS Hayden","year":"2008","unstructured":"Hayden MS, Ghosh S. Shared principles in NF-kappaB signaling. Cell. 2008;132:344\u201362.","journal-title":"Cell"},{"key":"3907_CR42","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1038\/sj.cdd.4401838","volume":"13","author":"ND Perkins","year":"2006","unstructured":"Perkins ND, Gilmore TD. Good cop, bad cop: the different faces of NF-kappaB. Cell Death Differ. 2006;13:759\u201372.","journal-title":"Cell Death Differ"},{"key":"3907_CR43","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1038\/nature09870","volume":"471","author":"TG Bivona","year":"2011","unstructured":"Bivona TG, Hieronymus H, Parker J, Chang K, Taron M, Rosell R, et al. FAS and NF-\u03baB signalling modulate dependence of lung cancers on mutant EGFR. Nature. 2011;471:523\u20136.","journal-title":"Nature"},{"key":"3907_CR44","doi-asserted-by":"publisher","first-page":"E2526","DOI":"10.1073\/pnas.1522612113","volume":"113","author":"CF Chiu","year":"2016","unstructured":"Chiu CF, Chang YW, Kuo KT, Shen YS, Liu CY, Yu YH, et al. NF-\u03baB-driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance. Proc Natl Acad Sci USA. 2016;113:E2526\u2013E2535.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3907_CR45","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1038\/s41392-024-01778-4","volume":"9","author":"J Zhang","year":"2024","unstructured":"Zhang J, Zhao K, Zhou W, Kang R, Wei S, Shu Y, et al. Tet methylcytosine dioxygenase 2 (TET2) deficiency elicits EGFR-TKI (tyrosine kinase inhibitors) resistance in non-small cell lung cancer. Signal Transduct Target Ther. 2024;9:65.","journal-title":"Signal Transduct Target Ther"},{"key":"3907_CR46","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.celrep.2015.03.012","volume":"11","author":"CM Blakely","year":"2015","unstructured":"Blakely CM, Pazarentzos E, Olivas V, Asthana S, Yan JJ, Tan I, et al. NF-\u03baB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep. 2015;11:98\u2013110.","journal-title":"Cell Rep"},{"key":"3907_CR47","doi-asserted-by":"publisher","first-page":"7331","DOI":"10.1111\/jcmm.14592","volume":"23","author":"Y Yang","year":"2019","unstructured":"Yang Y, Wang W, Chang H, Han Z, Yu X, Zhang T. Reciprocal regulation of miR-206 and IL-6\/STAT3 pathway mediates IL6-induced gefitinib resistance in EGFR-mutant lung cancer cells. J Cell Mol Med. 2019;23:7331\u201341.","journal-title":"J Cell Mol Med"},{"key":"3907_CR48","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.redox.2013.04.001","volume":"1","author":"SJ Chapple","year":"2013","unstructured":"Chapple SJ, Cheng X, Mann GE. Effects of 4-hydroxynonenal on vascular endothelial and smooth muscle cell redox signaling and function in health and disease. Redox Biol. 2013;1:319\u201331.","journal-title":"Redox Biol"},{"key":"3907_CR49","doi-asserted-by":"publisher","first-page":"1615","DOI":"10.1038\/cdd.2013.138","volume":"20","author":"S Dalleau","year":"2013","unstructured":"Dalleau S, Baradat M, Gu\u00e9raud F, Huc L. Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance. Cell Death Differ. 2013;20:1615\u201330.","journal-title":"Cell Death Differ"},{"key":"3907_CR50","doi-asserted-by":"publisher","first-page":"11611","DOI":"10.1074\/jbc.274.17.11611","volume":"274","author":"S Page","year":"1999","unstructured":"Page S, Fischer C, Baumgartner B, Haas M, Kreusel U, Loidl G, et al. 4-Hydroxynonenal prevents NF-\u03baB activation and tumor necrosis factor expression by inhibiting I\u03baB phosphorylation and subsequent proteolysis. J Biol Chem. 1999;274:11611\u20138.","journal-title":"J Biol Chem"},{"key":"3907_CR51","doi-asserted-by":"publisher","first-page":"18223","DOI":"10.1074\/jbc.M101266200","volume":"276","author":"C Ji","year":"2001","unstructured":"Ji C, Kozak KR, Marnett LJ. I\u03baB kinase, a molecular target for inhibition by 4-hydroxy-2-nonenal. J Biol Chem. 2001;276:18223\u20138.","journal-title":"J Biol Chem"},{"key":"3907_CR52","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2025.103719","volume":"85","author":"M Ioannidis","year":"2025","unstructured":"Ioannidis M, Tjepkema J, Uitbeijerse MRP, van den Bogaart G. Immunomodulatory effects of 4-hydroxynonenal. Redox Biol. 2025;85:103719.","journal-title":"Redox Biol"},{"key":"3907_CR53","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.bbrc.2016.03.064","volume":"473","author":"I Kobayashi","year":"2016","unstructured":"Kobayashi I, Takahashi F, Nurwidya F, Nara T, Hashimoto M, Murakami A, et al. Oct4 plays a crucial role in the maintenance of gefitinib-resistant lung cancer stem cells. Biochem Biophys Res Commun. 2016;473:125\u201332.","journal-title":"Biochem Biophys Res Commun"},{"key":"3907_CR54","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1111\/cas.12749","volume":"106","author":"S Hashida","year":"2015","unstructured":"Hashida S, Yamamoto H, Shien K, Miyoshi Y, Ohtsuka T, Suzawa K, et al. Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib. Cancer Sci. 2015;106:1377\u201384.","journal-title":"Cancer Sci"},{"key":"3907_CR55","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/s41392-024-01891-4","volume":"9","author":"J He","year":"2024","unstructured":"He J, Qiu Z, Fan J, Xie X, Sheng Q, Sui X. Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies. Signal Transd Target Ther. 2024;9:209.","journal-title":"Signal Transd Target Ther"},{"key":"3907_CR56","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1158\/1541-7786.MCR-21-0038","volume":"20","author":"C Leonce","year":"2022","unstructured":"Leonce C, Saintigny P, Ortiz-Cuaran S. Cell-Intrinsic Mechanisms of Drug Tolerance to Systemic Therapies in Cancer. Mol Cancer Res. 2022;20:11\u201329.","journal-title":"Mol Cancer Res"},{"key":"3907_CR57","doi-asserted-by":"publisher","first-page":"856","DOI":"10.3390\/antiox12040856","volume":"12","author":"L Milkovic","year":"2023","unstructured":"Milkovic L, Zarkovic N, Marusic Z, Zarkovic K, Jaganjac M. The 4-hydroxynonenal-protein adducts and their biological relevance: are some proteins preferred targets? Antioxidants. 2023;12:856.","journal-title":"Antioxidants"},{"key":"3907_CR58","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/s13045-022-01311-6","volume":"15","author":"K Shi","year":"2022","unstructured":"Shi K, Wang G, Pei J, Zhang J, Wang J, Ouyang L, et al. Emerging strategies to overcome resistance to third-generation EGFR inhibitors. J Hematol Oncol. 2022;15:94.","journal-title":"J Hematol Oncol"},{"key":"3907_CR59","doi-asserted-by":"publisher","first-page":"18825","DOI":"10.1039\/D3RA02347H","volume":"13","author":"MA Mansour","year":"2023","unstructured":"Mansour MA, AboulMagd AM, Abbas SH, Abdel-Rahman HM, Abdel-Aziz M. Insights into fourth-generation selective inhibitors of C797S EGFR mutation combating non-small cell lung cancer resistance: a critical review. RSC Adv. 2023;13:18825\u201353.","journal-title":"RSC Adv"},{"key":"3907_CR60","doi-asserted-by":"publisher","first-page":"19","DOI":"10.4062\/biomolther.2021.047","volume":"30","author":"KB Duggirala","year":"2022","unstructured":"Duggirala KB, Lee Y, Lee K. Chronicles of EGFR tyrosine kinase inhibitors: targeting EGFR C797S-containing triple mutations. Biomol Ther. 2022;30:19\u201327.","journal-title":"Biomol Ther"},{"key":"3907_CR61","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.891652","volume":"12","author":"TB Emran","year":"2022","unstructured":"Emran TB, Shahriar A, Mahmud AR, Rahman T, Abir MH, Siddiquee MFR, et al. Multidrug resistance in cancer: understanding molecular mechanisms and clinical implications. Front Oncol. 2022;12:891652.","journal-title":"Front Oncol"},{"key":"3907_CR62","doi-asserted-by":"publisher","first-page":"e007530","DOI":"10.1136\/jitc-2023-007530","volume":"11","author":"MF Soler","year":"2023","unstructured":"Soler MF, Abaurrea A, Azcoaga P, Araujo AM, Caffare MM. New perspectives in cancer immunotherapy: targeting IL-6 cytokine family. J Immunother Cancer. 2023;11:e007530.","journal-title":"J Immunother Cancer"},{"key":"3907_CR63","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1124\/pharmrev.120.000025","volume":"75","author":"JA Schulz","year":"2023","unstructured":"Schulz JA, Hartz AMS, Bauer B. ABCB1 and ABCG2 regulation at the blood-brain barrier: potential new targets to improve brain drug delivery. Pharmacol Rev. 2023;75:815\u201353.","journal-title":"Pharmacol Rev"},{"key":"3907_CR64","doi-asserted-by":"publisher","first-page":"C699","DOI":"10.1152\/ajpcell.00412.2025","volume":"329","author":"RA de Groot","year":"2025","unstructured":"de Groot RA, Reedijk D, Faucher Q, Mih\u0103il\u0103 SM, Masereeuw R. Strategies for overcoming ABC transporter-mediated multidrug resistance in colorectal cancer. Am J Physiol Cell Physiol. 2025;329:C699\u2013C717.","journal-title":"Am J Physiol Cell Physiol"},{"key":"3907_CR65","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2022.106487","volume":"185","author":"G Chen","year":"2022","unstructured":"Chen G, Zhu X, Li J, Zhang Y, Wang X, Zhang R, et al. Celastrol inhibits lung cancer growth by triggering histone acetylation and acting synergically with HDAC inhibitors. Pharmacol Res. 2022;185:106487.","journal-title":"Pharmacol Res"},{"key":"3907_CR66","doi-asserted-by":"publisher","first-page":"6500","DOI":"10.1158\/1078-0432.CCR-21-1652","volume":"27","author":"H Schwenzer","year":"2021","unstructured":"Schwenzer H, De Zan E, Elshani M, van Stiphout R, Kudsy M, Morris J, et al. The Novel Nucleoside Analogue ProTide NUC-7738 Overcomes Cancer Resistance Mechanisms In Vitro and in a First-In-Human Phase I Clinical Trial. Clin Cancer Res. 2021;27:6500\u201313.","journal-title":"Clin Cancer Res"},{"key":"3907_CR67","doi-asserted-by":"publisher","first-page":"5837","DOI":"10.1002\/ptr.7990","volume":"37","author":"Y Zhou","year":"2023","unstructured":"Zhou Y, Huang S, Guo Y, Ran M, Shan W, Chen WH, et al. Epigallocatechin gallate circumvents drug-induced resistance in non-small-cell lung cancer by modulating glucose metabolism and AMPK\/AKT\/MAPK axis. Phytother Res. 2023;37:5837\u201353.","journal-title":"Phytother Res"},{"key":"3907_CR68","doi-asserted-by":"publisher","first-page":"4885","DOI":"10.1158\/1078-0432.CCR-09-0109","volume":"15","author":"SA Milligan","year":"2009","unstructured":"Milligan SA, Burke P, Coleman DT, Bigelow RL, Steffan JJ, Carroll JL, et al. The green tea polyphenol EGCG potentiates the antiproliferative activity of c-Met and epidermal growth factor receptor inhibitors in non-small cell lung cancer cells. Clin Cancer Res. 2009;15:4885\u201394.","journal-title":"Clin Cancer Res"},{"key":"3907_CR69","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1038\/nature25016","volume":"552","author":"Z Skrott","year":"2017","unstructured":"Skrott Z, Mistr\u00edk M, Andersen KK, Friis S, Majera D, Gursky J, et al. Alcohol-abuse drug disulfiram targets cancer via p97 adaptor NPL4. Nature. 2017;552:194\u20139.","journal-title":"Nature"},{"key":"3907_CR70","doi-asserted-by":"publisher","first-page":"W488","DOI":"10.1093\/nar\/gkaa216","volume":"48","author":"A Ianevski","year":"2020","unstructured":"Ianevski A, Giri AK, Aittokallio T. SynergyFinder 2.0: visual analytics of multi-drug combination synergies (ZIP\/Loewe\/Bliss\/HSA). Nucleic Acids Res. 2020;48:W488\u2013W493.","journal-title":"Nucleic Acids Res"},{"key":"3907_CR71","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1038\/421691a","volume":"421","author":"EJ Calabrese","year":"2003","unstructured":"Calabrese EJ, Baldwin LA. Toxicology rethinks its central belief. Nature. 2003;421:691\u20132.","journal-title":"Nature"}],"container-title":["Oncogene"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41388-026-03907-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41388-026-03907-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41388-026-03907-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:04:43Z","timestamp":1787004283000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41388-026-03907-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,23]]},"references-count":71,"journal-issue":{"issue":"34","published-print":{"date-parts":[[2026,9,8]]}},"alternative-id":["3907"],"URL":"https:\/\/doi.org\/10.1038\/s41388-026-03907-5","relation":{},"ISSN":["0950-9232","1476-5594"],"issn-type":[{"value":"0950-9232","type":"print"},{"value":"1476-5594","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,23]]},"assertion":[{"value":"10 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 June 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 July 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors have declared no conflicts of interest.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"All experiments were approved by the Medical Ethics Committee of the Fujian Provincial Tumor Hospital (K2023-118-01). Experiments were conducted in accordance with relevant institutional guidelines and regulations.","order":2,"name":"Ethics","label":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}]}}