miR-146b-5p Enhances the Sensitivity of NSCLC to EGFR Tyrosine Kinase Inhibitors by Regulating the IRAK1/NF-κB Pathway

• Published in: Molecular therapy. Nucleic acids Vol. 22; pp. 471 - 483
• Main Authors: Liu, Yi-Nan, Tsai, Meng-Feng, Wu, Shang-Gin, Chang, Tzu-Hua, Tsai, Tzu-Hsiu, Gow, Chien-Hung, Wang, Hsin-Yi, Shih, Jin-Yuan
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 04.12.2020; American Society of Gene & Cell Therapy; Elsevier
• Subjects: EGFR TKI; IRAK1; microRNA; NF-κB; NSCLC; Original; resistance; NF-κB; microRNA; EGFR TKI; NSCLC; IRAK1; resistance
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2020.09.015

Although patients with non-small cell lung cancer harboring activating mutations in the epidermal growth factor receptor (EGFR) show good clinical response to EGFR tyrosine kinase inhibitors (TKIs), patients eventually develop acquired resistance. Previous studies have shown that several microRNAs (miRNAs) are involved in EGFR TKI resistance. Here, we aimed to investigate whether miR-146b-5p sensitizes the EGFR TKI-resistant lung cancer cells. Clinical analysis showed that miR-146b-5p expression in lung cancer cells isolated from pleural effusions of treatment-naive patients was significantly higher than that after acquiring resistance to EGFR TKI treatment. Ectopic expression of miR-146b-5p in EGFR TKI-resistant cells enhanced EGFR TKI-induced apoptosis. The same results were observed in EGFR-dependent and -independent osimertinib-resistant primary cancer cells (PE3479 and PE2988). Mechanically, miR-146b-5p suppressed nuclear factor κB (NF-κB) activity and NF-κB-related IL-6 and IL-8 production by targeting IRAK1. A negative correlation was observed between miR-146b-5p and IRAK1 in clinical specimens. In rescue experiments, restoration of IRAK1 expression reversed the effects of miR-146b-5p on EGFR TKI sensitivity and recovered NF-κB-regulated IL-6 and IL-8 production. In conclusion, miR-146b-5p/IRAK1/NF-κB signaling is important in promoting EGFR TKI resistance, and miR-146b-5p may be a useful tool for overcoming EGFR TKI resistance. [Display omitted] Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a challenge in the treatment of lung cancer. Alterations in microRNA (miR)-146b-5p and interleukin-1 receptor-associated kinase 1 (IRAK1) expression are implicated in acquired resistance to EGFR-TKIs. Based on our findings, ectopic miR-146b-5p overcomes EGFR TKI resistance in human lung cancer by targeting the IRAK1/nuclear factor κB (NF-κB) signaling pathway.