Cancer-associated fibroblasts promote osimertinib resistance in non‑small cell lung cancer cells via METTL1‑mediated NET1 m^7G modification
Cancer-associated fibroblasts promote osimertinib resistance in non‑small cell lung cancer cells via METTL1‑mediated NET1 m⁷G modification
Osimertinib resistance remains a major challenge in the treatment of non‑small cell lung cancer (NSCLC). In this study, it was found that CAFs promoted osimertinib resistance in NSCLC cells via elevating RNA m⁷G modification. Methyltransferase 1 (METTL1) in NSCLC cells mediated CAFs’ effect on m⁷G modification, and METTL1 was associated with NSCLC progression and poor prognosis. Further study demonstrates that CAFs upregulated METTL1 in NSCLC cells by secreting HMGB1. By applying MeRIP‑seq and RNA‑seq, neuroepithelial cell transforming gene 1 (NET1) was identified as a target of METTL1, and enhanced m⁷G modification of NET1 increased NET1 expression and activated downstream AKT/NF‑κB pathway. Importantly, reducing m⁷G modification by METTL1 knockdown significantly attenuated CAFs’ stimulatory effect on osimertinib resistance both in vitro and in vivo.
The study identifies a novel mechanism by which stromal CAFs confer resistance to osimertinib in NSCLC through METTL1‑driven m⁷G RNA modification of NET1, revealing a potential therapeutic target to overcome drug resistance.
Bizonyítékszint: Sejtvonalas. Laboratóriumi sejtekben vizsgálták.
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