miR-204 suppresses cancer stemness and enhances osimertinib sensitivity in non-small cell lung cancer by targeting CD44

• Published in: Molecular therapy. Nucleic acids Vol. 35; no. 1; p. 102091
• Main Authors: Wu, Shang-Gin, Chang, Tzu-Hua, Tsai, Meng-Feng, Liu, Yi-Nan, Huang, Yen-Lin, Hsu, Chia-Lang, Jheng, Han-Nian, Shih, Jin-Yuan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.03.2024; American Society of Gene & Cell Therapy; Elsevier
• Subjects: CD44; EGFR; EMT; epidermal growth factor receptor; epithelial-to-mesenchymal transition; miR-204; MT: Noncoding RNAs; Original; osimertinib resistance; stemness; TKI; tyrosine kinase inhibitor; miR-204; TKI; epidermal growth factor receptor; stemness; tyrosine kinase inhibitor; MT: Noncoding RNAs; EMT; CD44; osimertinib resistance; EGFR; epithelial-to-mesenchymal transition
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2023.102091

Osimertinib 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. [Display omitted] miR-204 reduced cancer stemness and the epithelial-to-mesenchymal transition, thus overcoming osimertinib resistance in lung cancer by inhibiting the CD44 signaling pathway. miR-204 may be a novel biomarker for predicting the treatment effectiveness of osimertinib in lung cancer treatment.