Loss of Key EMT-Regulating miRNAs Highlight the Role of ZEB1 in EGFR Tyrosine Kinase Inhibitor-Resistant NSCLC

• Published in: International journal of molecular sciences 2023-09, Vol.24 (19), p.14742
• Main Authors: Gohlke, Linus, Alahdab, Ahmad, Oberhofer, Angela, Worf, Karolina, Holdenrieder, Stefan, Michaelis, Martin, Cinatl, Jr, Jindrich, Ritter, Christoph A
• Format: Article
• Language: English
• Subjects: Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell culture; Cell Line, Tumor; DNA binding proteins; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug therapy; Epithelial-Mesenchymal Transition - genetics; ErbB Receptors - genetics; ErbB Receptors - metabolism; Erlotinib Hydrochloride - therapeutic use; Ethylenediaminetetraacetic acid; Genetic transcription; Humans; Kinases; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Medical prognosis; MicroRNA; MicroRNAs; MicroRNAs - metabolism; Microscopy; Mutation; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proteins; Stem cells; Tumors; Tyrosine; Tyrosine Kinase Inhibitors; Zinc Finger E-box-Binding Homeobox 1 - genetics
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241914742

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 was significantly overexpressed in all resistant cell lines. Transfection of a miR-205-5p mimic partially reversed EMT by inhibiting , restoring 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.