{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:39:24Z","timestamp":1792798764804,"version":"4.5.0"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), is effective in NSCLC patients with EGFR-activating or T790M mutations, but acquired resistance remains a major challenge. Although CCL2 has been implicated in EGFR-TKI resistance via AKT activation, the precise downstream mechanisms are not fully understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed malignant pleural effusion samples from patients with resistant NSCLC and conducted functional assays in lung cancer cell lines with ectopic CCL2 expression or knockdown, combined with\n                      <jats:italic>in vivo<\/jats:italic>\n                      xenograft models. Key downstream signaling pathways were interrogated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CCL2 was significantly upregulated in resistant patient samples. Overexpression of CCL2 induced osimertinib resistance, whereas silencing restored drug sensitivity. Mechanistically, CCL2 promoted resistance through STAT3- and ERK1\/2-dependent upregulation of ZEB1, rather than via the AKT pathway. Notably, combined STAT3 inhibition and osimertinib effectively reversed resistance in xenografts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings uncover a novel CCL2\u2013STAT3\u2013ZEB1 signaling axis that drives acquired osimertinib resistance in NSCLC. Dual targeting of STAT3 and EGFR may represent a promising therapeutic approach to improve clinical outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1699471","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T05:21:42Z","timestamp":1771564902000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["The STAT3\u2013ZEB1 axis contributes to CCL2-mediated resistance to osimertinib in lung cancer"],"prefix":"10.3389","volume":"16","author":[{"given":"Tzu-Hua","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Feng","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Da-Yeh University","place":["Changhua, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shang-Gin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital","place":["Taipei, Taiwan"]},{"name":"Department of Internal Medicine, National Taiwan University Cancer Center","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Nan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huey-Dong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Hsiu","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-Nian","family":"Jheng","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Lang","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Medical Research, National Taiwan University Hospital","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pu-Sheng","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Min-Sheng General Hospital","place":["Taoyuan, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Yuan","family":"Shih","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital","place":["Taipei, Taiwan"]},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(21)00312-3","article-title":"Lung cancer","volume":"398","author":"Thai","year":"2021","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3322\/caac.21763","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1586\/14737140.2016.1170596","article-title":"Platinum-based chemotherapy in advanced non-small-cell lung cancer: optimal number of treatment cycles","volume":"16","author":"Rossi","year":"2016","journal-title":"Expert Rev Anticancer Ther"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222312828","article-title":"The role of ereg\/egfr pathway in tumor progression","volume":"22","author":"Cheng","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0810699","article-title":"Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma","volume":"361","author":"Mok","year":"2009","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-12-2246","article-title":"Analysis of tumor specimens at the time of acquired resistance to egfr-tki therapy in 155 patients with egfr-mutant lung cancers","volume":"19","author":"Yu","year":"2013","journal-title":"Clin Cancer Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1703339","article-title":"Osimertinib in egfr T790m-positive lung cancer","volume":"376","author":"Mok","year":"2017","journal-title":"N Engl J Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1056\/NEJMoa1913662","article-title":"Overall survival with osimertinib in untreated, egfr-mutated advanced nsclc","volume":"382","author":"Ramalingam","year":"2020","journal-title":"N Engl J Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7189","article-title":"The mechanism of acquired resistance to irreversible egfr tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients","volume":"7","author":"Wu","year":"2016","journal-title":"Oncotarget"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-019-0573-8","article-title":"Resistance mechanisms to osimertinib in egfr-mutated non-small cell lung cancer","volume":"121","author":"Leonetti","year":"2019","journal-title":"Br J Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2020.07.014","article-title":"Mechanisms of osimertinib resistance and emerging treatment options","volume":"147","author":"Schmid","year":"2020","journal-title":"Lung Cancer"},{"key":"B12","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/s41467-018-08074-0","article-title":"Axl confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells","volume":"10","author":"Taniguchi","year":"2019","journal-title":"Nat Commun"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32487","article-title":"Acquired resistance to egfr tyrosine kinase inhibitors is mediated by the reactivation of stc2\/jun\/axl signaling in lung cancer","volume":"145","author":"Liu","year":"2019","journal-title":"Int J Cancer"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2019.01.025","article-title":"A novel cav1-met fusion in sclc transformation responds to crizotinib and osimertinib treatment","volume":"14","author":"Liu","year":"2019","journal-title":"J Thorac Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1200\/po.18.00126","article-title":"Acquired alk and ret gene fusions as mechanisms of resistance to osimertinib in egfr-mutant lung cancers","volume":"2","author":"Offin","year":"2018","journal-title":"JCO Precis Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-020-0457-8","article-title":"Tgf\u03b22-mediated epithelial-mesenchymal transition and nfKb pathway activation contribute to osimertinib resistance","volume":"42","author":"Jiang","year":"2021","journal-title":"Acta Pharmacol Sin"},{"key":"B17","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1186\/s12964-020-00589-8","article-title":"Ccl2\/ccr2 signaling in cancer pathogenesis","volume":"18","author":"Hao","year":"2020","journal-title":"Cell Commun Signal"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.01.012","article-title":"Chemokines and the immune response to cancer","volume":"54","author":"Ozga","year":"2021","journal-title":"Immunity"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14174251","article-title":"Cc chemokine ligand-2: A promising target for overcoming anticancer drug resistance","volume":"14","author":"Shi","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e13115","DOI":"10.1111\/cpr.13115","article-title":"Role of the ccl2-ccr2 signalling axis in cancer: mechanisms and therapeutic targeting","volume":"54","author":"Xu","year":"2021","journal-title":"Cell Prolif"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22168530","article-title":"Roles of ccl2-ccr2 axis in the tumor microenvironment","volume":"22","author":"Kadomoto","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.11778","article-title":"Ccl2 activates akt signaling to promote glycolysis and chemoresistance in glioma cells","volume":"46","author":"Qian","year":"2022","journal-title":"Cell Biol Int"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13876","article-title":"Ccl2 induces resistance to the antiproliferative effect of cabazitaxel in prostate cancer cells","volume":"110","author":"Natsagdorj","year":"2019","journal-title":"Cancer Sci"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2018.8769","article-title":"Ccl2 influences the sensitivity of lung cancer A549 cells to docetaxel","volume":"16","author":"Wang","year":"2018","journal-title":"Oncol Lett"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-015-2886-5","article-title":"Elevated circulating monocyte chemoattractant protein 1 (Mcp-1\/ccl-2) level may be an unfavorable predictive factor to platinum- and taxane-based combination chemotherapy in patients with gastric cancer","volume":"77","author":"Tas","year":"2016","journal-title":"Cancer Chemother Pharmacol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2014.03.016","article-title":"Enhancement of paclitaxel and carboplatin therapies by ccl2 blockade in ovarian cancers","volume":"8","author":"Moisan","year":"2014","journal-title":"Mol Oncol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3724\/abbs.2024106","article-title":"Ccl2 promotes egfr-tkis resistance in non-small cell lung cancer via the akt-emt pathway","volume":"56","author":"Diao","year":"2024","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2020.100773","article-title":"Epithelial-mesenchymal transition in cancer: A historical overview","volume":"13","author":"Ribatti","year":"2020","journal-title":"Transl Oncol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2018.02.016","article-title":"Androgen deprivation therapy-induced epithelial-mesenchymal transition of prostate cancer through downregulating spdef and activating ccl2","volume":"1864","author":"Tsai","year":"2018","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2015.106","article-title":"Mcp-1-induced erk\/gsk-3beta\/snail signaling facilitates the epithelial-mesenchymal transition and promotes the migration of mcf-7 human breast carcinoma cells","volume":"14","author":"Li","year":"2017","journal-title":"Cell Mol Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/2208176","article-title":"Chemokine\/gpcr signaling-mediated emt in cancer metastasis","volume":"2022","author":"Tian","year":"2022","journal-title":"J Oncol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"3995","DOI":"10.1158\/0008-5472.Can-14-0110","article-title":"The tgf\u03b2-mir200-mig6 pathway orchestrates the emt-associated kinase switch that induces resistance to egfr inhibitors","volume":"74","author":"Izumchenko","year":"2014","journal-title":"Cancer Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0454-2","article-title":"Epithelial-mesenchymal transition (Emt) beyond egfr mutations per se is a common mechanism for acquired resistance to egfr tki","volume":"38","author":"Weng","year":"2019","journal-title":"Oncogene"},{"key":"B34","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1186\/s13046-023-02726-w","article-title":"Axl in cancer: A modulator of drug resistance and therapeutic target","volume":"42","author":"Tang","year":"2023","journal-title":"J Exp Clin Cancer Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13163949","article-title":"The pathogenic role of pi3k\/akt pathway in cancer onset and drug resistance: an updated review","volume":"13","author":"Rascio","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aau8544","article-title":"Chronic tgf-B Exposure drives stabilized emt, tumor stemness, and cancer drug resistance with vulnerability to bitopic mtor inhibition","volume":"12","author":"Katsuno","year":"2019","journal-title":"Sci Signal"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2020.09.015","article-title":"Mir-146b-5p enhances the sensitivity of nsclc to egfr tyrosine kinase inhibitors by regulating the irak1\/nfKb pathway","volume":"22","author":"Liu","year":"2020","journal-title":"Mol Ther Nucleic Acids"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00167407","article-title":"Frequent epidermal growth factor receptor gene mutations in Malignant pleural effusion of lung adenocarcinoma","volume":"32","author":"Wu","year":"2008","journal-title":"Eur Respir J"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1038\/s41467-022-29292-7","article-title":"Knowledge graph-based recommendation framework identifies drivers of resistance in egfr mutant non-small cell lung cancer","volume":"13","author":"Gogleva","year":"2022","journal-title":"Nat Commun"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11010036","article-title":"Igfbp7 drives resistance to epidermal growth factor receptor tyrosine kinase inhibition in lung cancer","volume":"11","author":"Wu","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.3389","article-title":"Il-8 confers resistance to egfr inhibitors by inducing stem cell properties in lung cancer","volume":"6","author":"Liu","year":"2015","journal-title":"Oncotarget"},{"key":"B42","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1186\/s13046-019-1195-y","article-title":"The tgfbeta-mir-499a-shkbp1 pathway induces resistance to egfr inhibitors in osteosarcoma cancer stem cell-like cells","volume":"38","author":"Wang","year":"2019","journal-title":"J Exp Clin Cancer Res"},{"key":"B43","doi-asserted-by":"publisher","first-page":"3995","DOI":"10.1158\/0008-5472.CAN-14-0110","article-title":"The tgfbeta-mir200-mig6 pathway orchestrates the emt-associated kinase switch that induces resistance to egfr inhibitors","volume":"74","author":"Izumchenko","year":"2014","journal-title":"Cancer Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1172\/jci73048","article-title":"Cripto1 expression in egfr-mutant nsclc elicits intrinsic egfr-inhibitor resistance","volume":"124","author":"Park","year":"2014","journal-title":"J Clin Invest"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00419-w","article-title":"Tumor Microenvironment: An Evil Nexus Promoting Aggressive Head and Neck Squamous Cell Carcinoma and Avenue for Targeted Therapy","volume":"6","author":"Bhat","year":"2021","journal-title":"Signal Transduction and Targeted Therapy"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2022.121174","article-title":"Ccl2-targeted ginkgolic acid exerts anti-glioblastoma effects by inhibiting the jak3-stat1\/pi3k-akt signaling pathway","volume":"311","author":"Chen","year":"2022","journal-title":"Life Sci"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-24-0293","article-title":"Ccl2 expression predicts clinical outcomes and regulates E-cadherin and angiogenesis in pituitary tumours","volume":"32","author":"Silva","year":"2025","journal-title":"Endocrine-Related Cancer"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1111\/jop.12869","article-title":"Ccl2 promotes cell migration by inducing epithelial-mesenchymal transition in oral squamous cell carcinoma","volume":"48","author":"Ling","year":"2019","journal-title":"J Oral Pathol Med"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e13560","DOI":"10.1111\/cpr.13560","article-title":"Ccl2 promotes metastasis and epithelial-mesenchymal transition of non-small cell lung cancer via pi3k\/akt\/mtor and autophagy pathways","volume":"57","author":"Xu","year":"2024","journal-title":"Cell Prolif"},{"key":"B50","doi-asserted-by":"publisher","first-page":"21","DOI":"10.3892\/or.2017.6069","article-title":"Ccl2\/Ccr2 Axis Induces Hepatocellular Carcinoma Invasion and Epithelial-Mesenchymal Transition In vitro through Activation of the Hedgehog Pathway","volume":"39","author":"Zhuang","year":"2018","journal-title":"Oncol Rep"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2012.04.017","article-title":"Autocrine ccl2 promotes cell migration and invasion via pkc activation and tyrosine phosphorylation of paxillin in bladder cancer cells","volume":"59","author":"Chiu","year":"2012","journal-title":"Cytokine"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-024-03220-z","article-title":"Rbm15 facilitates osimertinib resistance of lung adenocarcinoma through M6a-dependent epigenetic silencing of spock1","volume":"44","author":"Li","year":"2025","journal-title":"Oncogene"},{"key":"B53","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1038\/s41419-024-07039-0","article-title":"Pim1 kinase promotes emt-associated osimertinib resistance via regulating gsk3\u03b2 Signaling pathway in egfr-mutant non-small cell lung cancer","volume":"15","author":"Zhou","year":"2024","journal-title":"Cell Death Dis"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1038\/s41467-023-35961-y","article-title":"Candidate mechanisms of acquired resistance to first-line osimertinib in egfr-mutated advanced non-small cell lung cancer","volume":"14","author":"Chmielecki","year":"2023","journal-title":"Nat Commun"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-005063","article-title":"Cd40\u00d7Her2 bispecific antibody overcomes the ccl2-induced trastuzumab resistance in her2-positive gastric cancer","volume":"10","author":"Sun","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.30446","article-title":"Sorafenib with asc-J9(\u00ae) synergistically suppresses the hcc progression via altering the pstat3-ccl2\/bcl2 signals","volume":"140","author":"Xu","year":"2017","journal-title":"Int J Cancer"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.1053\/j.gastro.2016.02.040","article-title":"Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib","volume":"150","author":"Zhou","year":"2016","journal-title":"Gastroenterology"},{"key":"B58","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1038\/s41419-020-03111-7","article-title":"Targeting tumor cell-derived ccl2 as a strategy to overcome bevacizumab resistance in etv5(+) colorectal cancer","volume":"11","author":"Feng","year":"2020","journal-title":"Cell Death Dis"},{"key":"B59","doi-asserted-by":"publisher","first-page":"Of1","DOI":"10.1158\/1078-0432.Ccr-21-4329","article-title":"Osimertinib plus selumetinib in egfr-mutated non-small cell lung cancer after progression on egfr-tkis: A phase ib, open-label, multicenter trial (Tatton part B)","volume":"28","author":"Yang","year":"2022","journal-title":"Clin Cancer Res"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.2217\/fon-2021-1406","article-title":"Insight 2: A phase ii study of tepotinib plus osimertinib in met-amplified nsclc and first-line osimertinib resistance","volume":"18","author":"Smit","year":"2022","journal-title":"Future Oncol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-17-1574","article-title":"Overcoming acquired resistance to azd9291, a third-generation egfr inhibitor, through modulation of mek\/erk-dependent bim and mcl-1 degradation","volume":"23","author":"Shi","year":"2017","journal-title":"Clin Cancer Res"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13236005","article-title":"The mek\/erk\/mir-21 signaling is critical in osimertinib resistance in egfr-mutant non-small cell lung cancer cells","volume":"13","author":"Huang","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B63","doi-asserted-by":"publisher","first-page":"djx014","DOI":"10.1093\/jnci\/djx014","article-title":"Co-activation of stat3 and yes-associated protein 1 (Yap1) pathway in egfr-mutant nsclc","volume":"109","author":"Chaib","year":"2017","journal-title":"J Natl Cancer Inst"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.Mct-12-0311","article-title":"Activation of il-6r\/jak1\/stat3 signaling induces de novo resistance to irreversible egfr inhibitors in non-small cell lung cancer with T790m resistance mutation","volume":"11","author":"Kim","year":"2012","journal-title":"Mol Cancer Ther"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.05.019","article-title":"Drug resistance via feedback activation of stat3 in oncogene-addicted cancer cells","volume":"26","author":"Lee","year":"2014","journal-title":"Cancer Cell"},{"key":"B66","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.tips.2015.10.001","article-title":"Feedback activation of stat3 as a cancer drug-resistance mechanism","volume":"37","author":"Zhao","year":"2016","journal-title":"Trends Pharmacol Sci"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104200","article-title":"Blockade of stat3\/il-4 overcomes egfr T790m-cis-L792f-induced resistance to osimertinib via suppressing M2 macrophages polarization","volume":"83","author":"Sun","year":"2022","journal-title":"EBioMedicine"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3390\/cells9010217","article-title":"Role of jak\/stat3 signaling in the regulation of metastasis, the transition of cancer stem cells, and chemoresistance of cancer by epithelial-mesenchymal transition","volume":"9","author":"Jin","year":"2020","journal-title":"Cells"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2024.5636","article-title":"Role of stat3 in cancer cell epithelial\u2212Mesenchymal transition (Review)","volume":"64","author":"Zhang","year":"2024","journal-title":"Int J Oncol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2014.01.004","article-title":"Honokiol inhibits epithelial\u2014Mesenchymal transition in breast cancer cells by targeting signal transducer and activator of transcription 3\/zeb1\/E-cadherin axis","volume":"8","author":"Avtanski","year":"2014","journal-title":"Mol Oncol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.295964","article-title":"Roles of stat3 and zeb1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition","volume":"287","author":"Xiong","year":"2012","journal-title":"J Biol Chem"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1172\/jci31871","article-title":"Mutations in the egfr kinase domain mediate stat3 activation via il-6 production in human lung adenocarcinomas","volume":"117","author":"Gao","year":"2007","journal-title":"J Clin Invest"},{"key":"B73","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.ccr.2007.12.020","article-title":"Autocrine il-6 signaling: A key event in tumorigenesis","volume":"13","author":"Grivennikov","year":"2008","journal-title":"Cancer Cell"},{"key":"B74","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1038\/s41419-018-0651-5","article-title":"Rnf25 promotes gefitinib resistance in egfr-mutant nsclc cells by inducing nfKb-mediated erk reactivation","volume":"9","author":"Cho","year":"2018","journal-title":"Cell Death Dis"},{"key":"B75","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.celrep.2015.03.012","article-title":"NfKb-activating complex engaged in response to egfr oncogene inhibition drives tumor cell survival and residual disease in lung cancer","volume":"11","author":"Blakely","year":"2015","journal-title":"Cell Rep"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.3956","article-title":"NfKb drives acquired resistance to a novel mutant-selective egfr inhibitor","volume":"6","author":"Galvani","year":"2015","journal-title":"Oncotarget"},{"key":"B77","doi-asserted-by":"publisher","first-page":"e0147344","DOI":"10.1371\/journal.pone.0147344","article-title":"Zeb1 mediates acquired resistance to the epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer","volume":"11","author":"Yoshida","year":"2016","journal-title":"PloS One"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12231","article-title":"A genetic cell context-dependent role for zeb1 in lung cancer","volume":"7","author":"Zhang","year":"2016","journal-title":"Nat Commun"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13164057","article-title":"Cd44 promotes lung cancer cell metastasis through erk-zeb1 signaling","volume":"13","author":"Wang","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B80","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1038\/s41419-021-03844-z","article-title":"Targeting stat3 signaling overcomes gefitinib resistance in non-small cell lung cancer","volume":"12","author":"Liu","year":"2021","journal-title":"Cell Death Dis"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1699471\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T05:21:43Z","timestamp":1771564903000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1699471\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,20]]},"references-count":80,"alternative-id":["10.3389\/fonc.2026.1699471"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1699471","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,20]]},"article-number":"1699471"}}