{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T01:18:50Z","timestamp":1789175930476,"version":"build-2803163510"},"reference-count":116,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T00:00:00Z","timestamp":1695945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DFG (German Research Foundation)"},{"name":"University of Greifswald"},{"name":"Frankfurter Stiftung f\u00fcr krebskranke Kinder"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Despite recent advances in the treatment of non-small cell lung cancer (NSCLC), acquired drug resistance to targeted therapy remains a major obstacle. Epithelial-mesenchymal transition (EMT) has been identified as a key resistance mechanism in NSCLC. Here, we investigated the mechanistic role of key EMT-regulating small non-coding microRNAs (miRNAs) in sublines of the NSCLC cell line HCC4006 adapted to afatinib, erlotinib, gefitinib, or osimertinib. The most differentially expressed miRNAs derived from extracellular vesicles were associated with EMT, and their predicted target ZEB1 was significantly overexpressed in all resistant cell lines. Transfection of a miR-205-5p mimic partially reversed EMT by inhibiting ZEB1, restoring CDH1 expression, and inhibiting migration in erlotinib-resistant cells. Gene expression of EMT-markers, transcription factors, and miRNAs were correlated during stepwise osimertinib adaptation of HCC4006 cells. Temporally relieving cells of osimertinib reversed transition trends, suggesting that the implementation of treatment pauses could provide prolonged benefits for patients. Our results provide new insights into the contribution of miRNAs to drug-resistant NSCLC harboring EGFR-activating mutations and highlight their role as potential biomarkers and therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms241914742","type":"journal-article","created":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T07:42:08Z","timestamp":1695973328000},"page":"14742","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Loss of Key EMT-Regulating miRNAs Highlight the Role of ZEB1 in EGFR Tyrosine Kinase Inhibitor-Resistant NSCLC"],"prefix":"10.3390","volume":"24","author":[{"given":"Linus","family":"Gohlke","sequence":"first","affiliation":[{"name":"Institute of Pharmacy, Clinical Pharmacy, University Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Alahdab","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Clinical Pharmacy, University Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Oberhofer","sequence":"additional","affiliation":[{"name":"Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University Munich, 80636 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3190-3873","authenticated-orcid":false,"given":"Karolina","family":"Worf","sequence":"additional","affiliation":[{"name":"Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University Munich, 80636 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9210-7064","authenticated-orcid":false,"given":"Stefan","family":"Holdenrieder","sequence":"additional","affiliation":[{"name":"Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University Munich, 80636 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5710-5888","authenticated-orcid":false,"given":"Martin","family":"Michaelis","sequence":"additional","affiliation":[{"name":"School of Biosciences, Division of Natural Sciences, University of Kent, Canterbury, Kent CT2 7NJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Jindrich","family":"Cinatl","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph A","family":"Ritter","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Clinical Pharmacy, University Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1002\/ijc.31937","article-title":"Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods","volume":"144","author":"Ferlay","year":"2019","journal-title":"Int. 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