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METTL16-dependent miR-146b-5p m6A modification remodeling sensitize NSCLC to osimertinib via activating PI3K/AKT

Hongyang Sang1, Jinlong Liu2,3, Xifang Chen4

  • 1Department of Cardiothoracic Surgery, Shanghai Sixth People's Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

BMC Cancer
|April 8, 2025
PubMed
Abstract

Insights

METTL16-mediated m6A modification of miR-146b-5p promotes non-small-cell lung cancer (NSCLC) proliferation and osimertinib resistance by activating the PI3K/AKT pathway. This finding offers a potential therapeutic target for overcoming NSCLC treatment resistance.

Area of Science:

  • Molecular Oncology
  • Cancer Therapeutics
  • Epigenetics

Background:

  • Non-small-cell lung cancer (NSCLC) presents a significant clinical challenge due to its poor prognosis and increasing resistance to targeted therapies like osimertinib.
  • Understanding the molecular mechanisms driving NSCLC progression and therapy resistance is crucial for developing effective treatment strategies.
  • MicroRNA (miRNA) dysregulation, particularly through epigenetic modifications like N6-methyladenosine (m6A), is implicated in cancer development and drug resistance.

Purpose of the Study:

  • To elucidate the role of miR-146b-5p m6A modification in NSCLC proliferation and osimertinib resistance.
  • To investigate the underlying molecular mechanisms, including its interaction with the PI3K/AKT signaling pathway.
  • To identify the specific methyltransferase responsible for miR-146b-5p m6A modification.

Main Methods:

  • Analysis of TCGA and GEO datasets to assess miR-146b-5p expression and its correlation with NSCLC prognosis.
  • In vitro experiments using NSCLC cell lines (A549, HCC827) to evaluate the functional impact of miR-146b-5p on proliferation and osimertinib sensitivity (proliferation assays, colony formation, IC50 assays).
  • Investigation of the regulatory mechanism involving the PI3K/AKT pathway using Western blots, dual-luciferase reporter assays, and rescue experiments.

Main Results:

  • miR-146b-5p was significantly upregulated in NSCLC tissues, correlating with a worse prognosis.
  • Overexpression of miR-146b-5p enhanced NSCLC cell proliferation and osimertinib resistance, while inhibition reversed these effects.
  • miR-146b-5p directly targets PTEN mRNA, leading to PI3K/AKT pathway activation; METTL16 was identified as the m6A methyltransferase for miR-146b-5p, promoting osimertinib resistance via this pathway.

Conclusions:

  • METTL16-mediated m6A modification of miR-146b-5p promotes NSCLC proliferation and osimertinib resistance by activating the PI3K/AKT signaling pathway.
  • This study highlights a novel epigenetic regulatory mechanism in NSCLC progression and drug resistance.
  • The findings suggest that targeting the METTL16/miR-146b-5p/PI3K/AKT axis could represent a promising therapeutic strategy for overcoming osimertinib resistance in NSCLC.
Keywords:
NSCLCOsimertinib resistancePI3K/AKTProliferationmiR-146b-5p

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