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). Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells in tumor microenvironment (TME), however, its role in osimertinib resistance in NSCLC is not fully understood. 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. Our study revealed a novel mechanism that CAFs conferred osimertinib resistance in NSCLC cells through modulating m⁷G modification. These findings underscore the importance of m⁷G modification in the communication between cancer cells and the TME, and pave the way for finding novel therapeutic strategies to overcome drug resistance by targeting m⁷G modification.