In Silico Analysis of Potential miRNAs-EGFR Binding Complex for EGFR-TKI Resistance Lung Cancer Cells.

INTRODUCTION

Overexpression of Epidermal Growth Factor Receptor (EGFR) plays a critical role in the progression and high mortality of Non-Small Cell Lung Cancer (NSCLC). Although EGFR tyrosine kinase inhibitors (EGFR-TKIs) demonstrate promising efficacy as first-line therapy, acquired resistance remains a major clinical challenge. Increasing evidence suggests that microRNAs (miRNAs) regulate EGFR signaling pathways and may influence therapeutic response and the development of resistance.

METHODS

This study aimed to identify EGFR-targeting microRNAs (miRNAs) and evaluate their binding stability using in silico approaches. Experimentally validated EGFR-targeting miRNAs were retrieved from miRTarBase and subsequently screened using miRDB and TargetScan based on their expression in lung adenocarcinoma cell lines. The secondary structures of miRNA-EGFR duplexes and three-dimensional structures of the miRNA-EGFR complexes were generated using RNAfold and RNAComposer, respectively. Binding affinity was evaluated using HNADOCK molecular docking. Further validation included survival and co-expression analyses using OncomiR and starBase, RNA-Binding Protein (RBP) interaction analysis using POSTAR3, and pathway enrichment analysis using DIANA-miRPath.

RESULTS

Three miRNAs-miR-7-5p, miR-133b, and miR-302b-3p were identified as potential regulators of EGFR. Molecular docking analysis demonstrated strong binding affinities, with docking scores of -339.30, -476.76, and -491.18 kcal/mol, respectively. Survival analysis revealed no significant association between the expression of these miRNAs and patient prognosis. In contrast, co-expression analysis demonstrated a significant correlation between miR-133b and EGFR expression. Several upregulated RNA- Binding Proteins (RBPs) that interact with EGFR were identified, suggesting enhanced post-transcriptional regulation that may contribute to the development of EGFR-TKI resistance. Pathway enrichment analysis further identified hsa-miR-7-5p as being significantly associated with EGFR-mediated PI3K-Akt signaling and the NSCLC pathway.

DISCUSSION: These findings highlight candidate miRNAs as potential regulators of EGFR signaling and possible biomarkers influencing targeted therapy response.

CONCLUSION

Further experimental and clinical validation is required to confirm their therapeutic relevance in EGFR-TKI-resistant lung cancer.