AKT1 Functional Polymorphism (rs2494750) Influences Clinical Outcomes in Patients With Advanced Lung Cancer Treated With EGFR Inhibitors

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for patients with advanced lung cancer harboring activating EGFR mutations. This study aimed to investigate the association between genetic polymorphisms in the EGFR signaling pathway and clinical outcomes in patients receiving EGFR-TKI therapy. METHODS: We enrolled 266 patients with advanced lung cancer treated with EGFR-TKIs and examined 30 putative functional polymorphisms across 11 genes involved in the EGFR signaling pathway. Associations between these polymorphisms and clinical outcomes were assessed. RESULTS: Among the polymorphisms analyzed, AKT1 rs2494750G>C was significantly associated with improved chemotherapy response (codominant model: odds ratio, 1.78; 95% confidence interval [CI], 1.05-2.99; P = 0.031) and prolonged progression-free survival (recessive model: hazard ratio, 0.62; 95% CI, 0.39-0.97; P = 0.037). In the luciferase reporter assays, the rs2494750C allele exhibited significantly lower promoter activity than the rs2494750G allele in H522 and A549 lung cancer cell lines (P = 0.033 and P < 0.001, respectively). AKT1 expression levels were also significantly reduced in individuals with the CC genotype compared to those with GG or GC genotypes (P = 0.034). CONCLUSION: The AKT1 rs2494750G>C polymorphism reduces promoter activity and gene expression of AKT1, potentially contributing to improved clinical outcomes in patients with advanced lung cancer treated with EGFR-TKIs.