TET2 repression contributes to EGFR TKI resistance in EGFR-mutant non-small cell lung cancer through regulating AXIN2...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are standard treatments for non-small cell lung cancer (NSCLC).
• Acquired resistance to EGFR TKIs remains a significant clinical challenge.
• TET2 mutations have been observed in EGFR TKI-resistant NSCLC, but their role is not fully understood.

Purpose of the Study:

• To investigate the molecular mechanism by which TET2 loss-of-function contributes to EGFR TKI resistance in NSCLC.
• To identify specific genes and pathways involved in TET2-mediated drug resistance.
• To explore potential therapeutic strategies to overcome EGFR TKI resistance.

Main Methods:

• Targeted next-generation sequencing in NSCLC patients.
• Reduced representation bisulfite sequencing (RRBS) to analyze global DNA methylation.
• TET2 knockdown (KD) in PC9 lung cancer cells.
• Bioinformatic analysis (GO, KEGG) for functional enrichment.
• RT-PCR for gene expression validation.
• In vivo studies using mouse models.

Main Results:

• TET2 mutations were detected in 11% of T790M-negative EGFR TKI-resistant NSCLC patients.
• TET2 knockdown in PC9 cells decreased sensitivity to gefitinib and attenuated apoptosis.
• RRBS identified 43 hypermethylated genes in TET2 KD cells, including AXIN2 and CSK.
• AXIN2 knockdown mimicked the gefitinib resistance phenotype.
• Decitabine (DCA) reversed gefitinib resistance in TET2 KD cells and mouse models.

Conclusions:

• TET2 loss-of-function promotes EGFR TKI resistance in NSCLC through promoter hypermethylation and downregulation of genes like AXIN2.
• AXIN2 methylation is a novel mechanism contributing to gefitinib resistance.
• Demethylation agents like decitabine show potential in overcoming TET2-driven EGFR TKI resistance in NSCLC.