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AKT1 Functional Polymorphism (rs2494750) Influences Clinical Outcomes in Patients With Advanced Lung Cancer Treated
Sun Ha Choi1,2,3, Jin Eun Choi1, Mi Jeong Hong1
1Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea.
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.
Insights
A specific genetic variation in the AKT1 gene (rs2494750G>C) is linked to better treatment response and longer progression-free survival for advanced lung cancer patients receiving EGFR-TKI therapy.
Area of Science:
- Oncology
- Genetics
- Pharmacogenomics
Background:
- Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatment for advanced lung cancer with EGFR mutations.
- Genetic variations in the EGFR signaling pathway may influence treatment efficacy.
Purpose of the Study:
- To investigate the association between genetic polymorphisms in the EGFR signaling pathway and clinical outcomes in patients treated with EGFR-TKIs.
Main Methods:
- Analyzed 30 functional polymorphisms in 11 genes of the EGFR pathway in 266 advanced lung cancer patients receiving EGFR-TKIs.
- Assessed associations between polymorphisms and clinical outcomes, including chemotherapy response and progression-free survival.
- Utilized luciferase reporter assays and measured AKT1 expression levels to understand the functional impact of identified polymorphisms.
Main Results:
- The AKT1 rs2494750G>C polymorphism was significantly associated with improved chemotherapy response (OR 1.78, P=0.031) and prolonged progression-free survival (HR 0.62, P=0.037).
- The rs2494750C allele showed reduced promoter activity in lung cancer cell lines (P=0.033 and P<0.001).
- Individuals with the CC genotype had significantly reduced AKT1 expression levels (P=0.034).
Conclusions:
- The AKT1 rs2494750G>C polymorphism reduces AKT1 promoter activity and gene expression.
- This genetic variation may contribute to improved clinical outcomes in advanced lung cancer patients treated with EGFR-TKIs.
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