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Cancer-associated fibroblasts promote osimertinib resistance in non-small cell lung cancer cells via METTL1-mediated

Yongmei Qian1,2,3, Zhiyuan Gong1,2, Yidan Jia1,2

  • 1Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.

Cell Death & Disease
|February 21, 2026
PubMed

Insights

Cancer-associated fibroblasts (CAFs) drive osimertinib resistance in non-small cell lung cancer (NSCLC) by increasing RNA m7G modification. Targeting METTL1-mediated m7G modification offers a new strategy against drug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Osimertinib resistance is a significant hurdle in treating non-small cell lung cancer (NSCLC).
  • Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME), but their role in drug resistance is not fully elucidated.

Purpose of the Study:

  • To investigate the mechanism by which CAFs contribute to osimertinib resistance in NSCLC.
  • To identify molecular targets for overcoming this resistance.

Main Methods:

  • Utilized cell culture and in vivo models.
  • Employed RNA sequencing (RNA-seq) and m6A individual-nucleotide resolution crosslinking and immunoprecipitation sequencing (MeRIP-seq).
  • Performed gene knockdown experiments (METTL1).

Main Results:

  • CAFs promote osimertinib resistance in NSCLC cells by upregulating RNA N6-methyladenosine (m7G) modification.
  • METTL1 mediates this effect, with its expression linked to poor prognosis.
  • CAFs secrete HMGB1 to upregulate METTL1, which targets NET1, activating the AKT/NF-κB pathway.
  • METTL1 knockdown significantly reduced CAFs' pro-resistance effects.

Conclusions:

  • CAFs confer osimertinib resistance in NSCLC via modulation of m7G modification.
  • This highlights the role of m7G modification in cancer cell-TME communication.
  • Targeting m7G modification presents a potential therapeutic strategy to overcome drug resistance in NSCLC.

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