M6A Methylation Regulators METTL3 and ALKBH5 are Risk Factors for EGFR-Mutant NSCLC

IntroductionNon-small cell lung cancer (NSCLC), which accounts for >85% of all lung cancers, is the most common solid malignant tumor, with high morbidity and mortality worldwide. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment is widely used clinically because the epidermal growth factor receptor (EGFR) is the main driver gene of lung cancer; however, the development of drug resistance is inevitable. Epigenetic abnormalities can also lead to tyrosine kinase inhibitor (TKI) resistance. However, the relationship between N6-methyladenosine (m6A)-related proteins and EGFR mutations in NSCLC and their clinical significance remain unclear. In this retrospective study, the expression of m6A-related regulatory factors in patients with EGFR mutations were analyzed to investigate their relationship with clinicopathological features and prognoses.MethodsThe association between m6A-related regulatory factors and NSCLC was analyzed using data derived from The Cancer Genome Atlas, case collection, follow-up, immunohistochemistry, and scoring.ResultsA total of 246 NSCLC specimens were examined in this study. Among these, 143 EGFR-mutant cases exhibited significantly higher expression of METTL3 and ALKBH5 compared to EGFR-wildtype specimens. The median progression-free survival time of patients with high METTL3 expression (SI >6) was 25.0 months, and that of patients with high ALKBH5 expression (SI >6) was 24.1 months in EGFR-mutant cases. High METTL3 and ALKBH5 expression levels are independent risk factors for progression-free survival in patients with EGFR mutations. The median progression-free survival time of patients with EGFR mutations was 45.7 months in those with high expression of METTL3 or ALKBH5 alone, whereas it decreased to 20.1 months in those with high simultaneous expression of METTL3 and ALKBH5.ConclusionsMETTL3 and ALKBH5 were upregulated in NSCLC tissues with EGFR mutations and significantly correlated with poor prognoses. Thus, METTL3 and ALKBH5 may serve as prognostic biomarkers in EGFR-mutant NSCLC.