The N6-methyladenosine-mediated cLMNB1 degrades FGFR4 to overcome osimertinib resistance in non-small cell lung cancer.

Osimertinib resistance is the main challenge in treating EGFR-mutant lung adenocarcinoma (LUAD). The role of N6-methyladenosine (m6A) modification of circular RNAs (circRNAs) in osimertinib-resistant LUAD remains largely unknown. We used MeRIP-seq and circRNA-seq to screen for potential circRNA candidates that influence osimertinib resistance. It was observed that circRNA LMNB1 (cLMNB1) increased the sensitivity of LUAD to osimertinib in vitro and in vivo. Mechanistically, cLMNB1 acts as a scaffold between fibroblast growth factor receptor 4 (FGFR4) and E3 ubiquitin-protein ligase CBL (c-Cbl), enhancing the ubiquitin-dependent degradation of FGFR4. Furthermore, METTL3 and YTHDF2 are responsible for increased m6A modification levels and decreased cLMNB1 expression in osimertinib-resistant LUAD without affecting its functions. Our findings demonstrate that cLMNB1, mediated by m6A modification, overcomes osimertinib resistance by destabilizing the FGFR4 protein in LUAD. cLMNB1 with an m6A modification site mutation (cLMNB1-mut) could be a promising nucleic acid drug, as it has shown excellent efficacy in osimertinib-resistant preclinical models of LUAD.