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

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.