Phosphorylation of AGO2 by TBK1 Promotes the Formation of Oncogenic MiRISC in NSCLC

Overview

Journal Adv Sci (Weinh)

Specialty Biomedical Engineering

Date 2024 Feb 14

PMID 38351659

Authors

Xian Zhao

Yingting Cao

Runhui Lu

Zihan Zhou

Caihu Huang

Lian Li

Jiayi Huang

Ran Chen

Yanli Wang

Jian Huang

Jinke Cheng

Junke Zheng

Yujie Fu

Jianxiu Yu

Affiliations

Soon will be listed here.

Abstract

Non-small-cell lung cancer (NSCLC) is a highly lethal tumor that often develops resistance to targeted therapy. It is shown that Tank-binding kinase 1 (TBK1) phosphorylates AGO2 at S417 (pS417-AGO2), which promotes NSCLC progression by increasing the formation of microRNA-induced silencing complex (miRISC). High levels of pS417-AGO2 in clinical NSCLC specimens are positively associated with poor prognosis. Interestingly, the treatment with EGFR inhibitor Gefitinib can significantly induce pS417-AGO2, thereby increasing the formation and activity of oncogenic miRISC, which may contribute to NSCLC resistance to Gefitinib. Based on these, two therapeutic strategies is developed. One is jointly to antagonize multiple oncogenic miRNAs highly expressed in NSCLC and use TBK1 inhibitor Amlexanox reducing the formation of oncogenic miRISC. Another approach is to combine Gefitinib with Amlexanox to inhibit the progression of Gefitinib-resistant NSCLC. This findings reveal a novel mechanism of oncogenic miRISC regulation by TBK1-mediated pS417-AGO2 and suggest potential therapeutic approaches for NSCLC.

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