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Lomitapide: Targeting METTL3 to Overcome Osimertinib Resistance in NSCLC Through Autophagy Activation
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Lomitapide: Targeting METTL3 to Overcome Osimertinib Resistance in NSCLC Through Autophagy Activation
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Journal Article
Lomitapide: Targeting METTL3 to Overcome Osimertinib Resistance in NSCLC Through Autophagy Activation
2025
Overview
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. 1. Lomitapide can significantly inhibit the methyltransferase activity of METTL3 and reduce the m6A modification and expression of UQCC2. 2. The METTL3/UQCC2 axis inhibition by lomitapide could activate autophagy‐mediated cell death, thus reversing osimertinib resistance in NSCLC cells.
Publisher
John Wiley & Sons, Inc,Wiley
Subject
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