Lomitapide: Targeting METTL3 to Overcome Osimertinib Resistance in NSCLC Through Autophagy Activation

Abstract

Osimertinib resistance remains a significant challenge in the treatment of non-small cell lung cancer (NSCLC). N⁶-methyladenosine (m⁶A) modifications are closely linked to various mechanisms of anticancer resistance and autophagy, offering new avenues for targeted therapies. However, the role of m⁶A-mediated autophagy in osimertinib-resistant NSCLC is still unclear. In this study, we utilized multi-omics sequencing analysis and found that overexpression of the m⁶A methyltransferase METTL3 contributes to osimertinib resistance in NSCLC. Importantly, we identified that METTL3 positively regulates the expression of the autophagy-related gene ubiquinone-cytochrome C reductase complex assembly factor 2 (UQCC2) through an m⁶A-dependent mechanism. Further, we confirmed that METTL3 knockdown leads to UQCC2 downregulation and triggers autophagy activation. Interestingly, lomitapide, a cholesterol-lowering drug, was repurposed to enhance the sensitivity of cancer cells to therapy by inhibiting METTL3, which in turn activated autophagy-associated cell death pathways, reversing osimertinib resistance. This study emphasizes the critical role of the METTL3/UQCC2 axis in autophagy-mediated drug resistance and positions lomitapide as a promising METTL3 inhibitor and autophagy inducer with potential therapeutic effects, either alone or in combination with other anticancer agents, in patients with osimertinib-resistant NSCLC.