Lung cancer ranks first in both incidence and mortality among malignant tumors in China, with lung adenocarcinoma closely associated with epidermal growth factor receptor (EGFR) gene mutations. Currently, effective targeted therapies exist for patients with EGFR-sensitive mutations, yet drug resistance remains an unavoidable challenge. Fructose-1, 6-bisphosphate aldolase A (ALDOA) is a key glycolytic enzyme highly expressed in multiple cancers. The relationship between ALDOA and targeted drug resistance as well as prognosis in lung adenocarcinoma remains unclear.

This study investigating the expression of ALDOA in targeted therapy-resistant lung cancer patients and its relationship with clinical and pathological characteristics.

Based on the TCGA database, data from 483 lung adenocarcinoma tissues and 59 normal lung tissues were collected. Samples were divided into high-and low-expression groups according to the median ALDOA expression level (239 cases each; 5 cases with missing data were excluded). The difference between ALDOA expression levels and overall survival in both groups was evaluated. Thirty patients with lung adenocarcinoma who developed resistance to targeted treatment with Icotinib at the Affiliated Cancer Hospital of Xinjiang Medical University between October 2016 and May 2024 were enrolled. Tumor biopsy or lymph node biopsy spec imens and clinical data were collected. ALDOA expression levels in the specimens were detected using immunohistochemical staining. Patients were categorized into high-expression (n=21) and low-expression (n=9) groups based on ALDOA levels. To analyze and compare the prognosis between the two patient groups, univariate Cox proportional hazards regression analysis was employed to identify factors influencing PFS after targeted therapy resistance in lung adenocarcinoma patients. Survival analysis was performed using the Log-rank test, and PFS survival curves were plotted using the Kaplan-Meier method.

Analysis based on the TCGA database revealed that ALDOA expression levels were higher in lung adenocarcinoma tissues than in normal lung tissues (P<0.05). Furthermore, the overall survival (OS) of the high ALDOA expression group was lower than that of the low expression group (HR=1.8, P<0.001). Comparisons of ALDOA expression levels among patients with different clinical stages (Ⅰ-Ⅳ) revealed statistically significant differences (F=5.98, P<0.001). Immunohistochemical analysis revealed that ALDOA protein expression scores were higher in lung cancer biopsy specimens after drug resistance compared to before resistance (paired t-test=4.104, P<0.001). Comparing disease response, results showed ALDOA high-expression group demonstrated a lower ORR than ALDOA low-expression group (P=0.045). Survival analysis revealed longer PFS in the ALDOA low-expression group compared to the high-expression group. Log-rank test results demonstrated a statistically significant difference between the two groups (χ²=5.413, P=0.02). Univariate Cox proportional hazards regression analysis revealed that low ALDOA expression was a protective factor for PFS after targeted therapy resistance in lung cancer (HR=0.066, 95%CI=0.007-0.648, P<0.05); Lymph node metastasis status (N2 and N3) was a risk factor for PFS after targeted therapy resistance in lung cancer (HR=14.015, 95%CI=2.017-97.379, P<0.05).

Upregulation of ALDOA expression following targeted drug therapy represents a significant feature of drug resistance, with its high expression closely associated with poor patient prognosis during targeted treatment. This suggests the protein may serve as a potiential biomarker for predicting treatment failure with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI).