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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Copy Number Amplification and c-Myc Transcriptional Activation-Mediated RNA-Binding Protein MEX3A Promotes EGFR-TKI

Shi Xiling1, Du Lin1, Dai Jiali1

  • 1Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.

Thoracic Cancer
|May 4, 2026
PubMed
Abstract

Insights

RNA-binding protein MEX3A drives acquired resistance to EGFR-TKIs in non-small-cell lung cancer (NSCLC). Both gene amplification and c-Myc activation contribute to MEX3A

Area of Science:

  • Molecular Oncology
  • Cancer Genomics
  • Drug Resistance Mechanisms

Background:

  • Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are crucial for non-small-cell lung cancer (NSCLC) treatment.
  • Acquired resistance to EGFR-TKIs remains a significant clinical challenge in NSCLC management.
  • The molecular drivers of acquired resistance are not fully elucidated.

Purpose of the Study:

  • To investigate the role of RNA-binding protein MEX3A in acquired resistance to EGFR-TKIs in NSCLC.
  • To elucidate the activation mechanisms of MEX3A in the context of EGFR-TKI resistance.

Main Methods:

  • Analysis of paired tumor specimens from 18 advanced NSCLC patients with EGFR mutations.
  • In vitro functional assays (CCK-8, colony formation) to assess MEX3A's impact on TKI sensitivity.
  • Genomic analysis (CNV, qRT-PCR) and transcriptional analysis (c-Myc, Western blotting, ChIP) to determine MEX3A activation pathways.
  • In vivo evaluation using a xenograft tumor model to assess MEX3A knockdown effects.

Main Results:

  • MEX3A was significantly upregulated in TKI-resistant NSCLC tissues, correlating with poorer survival.
  • MEX3A overexpression promoted EGFR-TKI resistance both in vitro and in vivo.
  • MEX3A activation was driven by copy number amplification and c-Myc-dependent transcriptional regulation.

Conclusions:

  • MEX3A is a key mediator of acquired EGFR-TKI resistance in NSCLC.
  • Genomic copy number amplification and c-Myc transcriptional activity are crucial for MEX3A activation in TKI resistance.
  • MEX3A represents a potential therapeutic target for overcoming EGFR-TKI resistance in NSCLC.
Keywords:
EGFR‐TKIcopy number amplificationnon–small‐cell lung cancerRBP

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