Copy Number Amplification and c‐Myc Transcriptional Activation‐Mediated <scp>RNA</scp> ‐Binding Protein <scp>MEX3A</scp> Promotes <scp>EGFR</scp> ‐ <scp>TKI</scp> Resistance in Non–Small‐Cell Lung Cancer

OBJECTIVE: To investigate the functional role and activation mechanisms of RNA-binding protein MEX3A in acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC). METHODS: Paired tumor specimens were from 18 advanced NSCLC patients with sensitizing EGFR mutations before treatment and after developing TKI resistance. In vitro functional assays, including CCK-8 and colony formation, were conducted to evaluate the impact of MEX3A on EGFR-TKI sensitivity. At the genomic level, copy number variation (CNV) analysis and quantitative real-time PCR (qRT-PCR) validated the genomic relationship between MEX3A copy number and expression. Transcriptional regulation by c-Myc was examined via qRT-PCR, Western blotting, and chromatin immunoprecipitation (ChIP). Finally, the in vivo effects of MEX3A knockdown on tumor growth and TKI sensitivity were evaluated using a xenograft tumor model. RESULTS: MEX3A was significantly upregulated in TKI-resistant tissues, correlating with poorer survival. MEX3A promoted EGFR-TKI resistance of NSCLC, both in vitro and in vivo. Mechanistically, at the genomic level, copy number amplification can drive the activation of MEX3A, and at the transcriptional level, the transcription factor c-Myc can activate its expression. CONCLUSION: MEX3A is a key molecule that promotes acquired EGFR-TKI resistance in NSCLC. Its activation is mediated by both genomic copy number amplification and c-Myc-dependent transcriptional regulation, thereby clarifying the activation reasons of MEX3A in TKI resistance at two levels. Our findings suggest that MEX3A may serve as a potential therapeutic target for overcoming TKI resistance in NSCLC.