METTL14-Mediated Bim mRNA m6A Modification Augments Osimertinib Sensitivity in EGFR -Mutant NSCLC Cells

Jul 2, 2024Molecular cancer research : MCR

How METTL14 Changes Bim mRNA to Increase Osimertinib Sensitivity in Lung Cancer Cells with EGFR Mutations

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Abstract

Decreased expression of the m6A methyltransferase METTL14 is significantly associated with osimertinib resistance in non-small cell lung cancer.

Resistance to osimertinib in NSCLC may be linked to reduced levels of m6A methylation due to low METTL14 expression.
Specific reduction of METTL14 was shown to induce osimertinib resistance in both laboratory and animal models.
Increasing METTL14 expression restored the effectiveness of osimertinib in resistant NSCLC cells.
METTL14 is involved in stabilizing and increasing the expression of the Bim mRNA, which plays a role in promoting cell death in response to osimertinib.
Clinical samples indicate that lower METTL14 levels correlate with worse outcomes in patients with osimertinib-resistant NSCLC.

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Resistance to osimertinib represents a significant challenge for the successful treatment of non-small cell lung cancer (NSCLC) harboring activating mutations in EGFR. N6-methyladenosine (m6A) on mRNAs is critical for various biological processes, yet whether m6A regulates osimertinib resistance of NSCLC remains unknown. In this study, we demonstrated that developing osimertinib-resistant phenotypes depends on m6A reduction resulting from downexpression of m6A methyltransferase METTL14 in EGFR-mutant NSCLCs. Both in vitro and in vivo assays showed that specific knockdown of METTL14 was sufficient to confer osimertinib resistance and that elevated expression of METTL14 rescued the efficacy of osimertinib in the resistant NSCLC cells. Mechanistically, METTL14 promoted m6A methylation of pro-apoptotic Bim mRNA and increased Bim mRNA stability and expression, resulting in activating the Bim-dependent pro-apoptotic signaling and thereby promoting osimertinib-induced cell apoptosis. Analysis of clinical samples revealed that decreased expression of METTL14 was observed in osimertinib-resistant NSCLC tissues and significantly associated with a poor prognosis. In conclusion, our study reveals a novel regulatory mechanism by which METTL14-mediated m6A methylation of Bim mRNA inhibited osimertinib resistance of NSCLC cells. It offers more evidences for the involvement of m6A modification in regulation of osimertinib resistance and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR tyrosine kinase inhibitors. Implications: This study offers more evidences for the involvement of METTL14-mediated N6-methyladenosine modification in regulation of osimertinib resistance and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR tyrosine kinase inhibitors.

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METTL14-Mediated Bim mRNA m6A Modification Augments Osimertinib Sensitivity in EGFR -Mutant NSCLC Cells

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