SHANG-GIN WUChang, Tzu-HuaTzu-HuaChangTsai, Meng-FengMeng-FengTsaiLiu, Yi-NanYi-NanLiuYEN-LIN HUANGHsu, Chia-LangChia-LangHsuJheng, Han-NianHan-NianJhengJIN-YUAN SHIH2024-02-232024-02-232024-03-122162-2531https://scholars.lib.ntu.edu.tw/handle/123456789/639916Osimertinib is an effective treatment option for patients with advanced non-small cell lung cancer (NSCLC) with EGFR activation or T790M resistance mutations; however, acquired resistance to osimertinib can still develop. This study explored novel miRNA-mRNA regulatory mechanisms that contribute to osimertinib resistance in lung cancer. We found that miR-204 expression in osimertinib-resistant lung cancer cells was markedly reduced compared to that in osimertinib-sensitive parental cells. miR-204 expression levels in cancer cells isolated from treatment-naive pleural effusions were significantly higher than those in cells with acquired resistance to osimertinib. miR-204 enhanced the sensitivity of lung cancer cells to osimertinib and suppressed spheroid formation, migration, and invasion of lung cancer cells. Increased miR-204 expression in osimertinib-resistant cells reversed resistance to osimertinib and enhanced osimertinib-induced apoptosis by upregulating BIM expression levels and activating caspases. Restoration of CD44 (the direct downstream target gene of miR-204) expression reversed the effects of miR-204 on osimertinib sensitivity, recovered cancer stem cell and mesenchymal markers, and suppressed E-cadherin expression. The study demonstrates that miR-204 reduced cancer stemness and epithelial-to-mesenchymal transition, thus overcoming osimertinib resistance in lung cancer by inhibiting the CD44 signaling pathway.enCD44; EGFR; EMT; MT: Noncoding RNAs; TKI; epidermal growth factor receptor; epithelial-to-mesenchymal transition; miR-204; osimertinib resistance; stemness; tyrosine kinase inhibitormiR-204 suppresses cancer stemness and enhances osimertinib sensitivity in non-small cell lung cancer by targeting CD44journal article10.1016/j.omtn.2023.102091381303722-s2.0-85179932552https://api.elsevier.com/content/abstract/scopus_id/85179932552