Abstract: Background　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. Objective　This study investigating the Expression of ALDOA in Targeted Therapy-Resistant Lung Cancer Patients and Its Relationship with Clinical and Pathological Characteristics. Methods　Based on the TCGA database, data from 483 lung adenocarcinoma tissues and 387 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 Cancer Hospital Affiliated to Xinjiang Medical University between October 2016 and May 2024 were enrolled. Tumor biopsy or lymph node biopsy specimens 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. Results　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=2.0179-7.379, P<0.05). Conclusion　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-TKIs).

Key words: Lung cancer, Fructose-bisphosphate aldolase A, Targeted therapy, Drug resistance, Prognosis

摘要： 背景　肺癌在我国恶性肿瘤中发病率和死亡率均位居首位，其中肺腺癌与表皮生长因子受体（EGFR）基因突变关系密切。目前，针对EGFR敏感突变的患者已经有较为成熟的靶向治疗方案，但耐药问题仍不可避免。果糖二磷酸醛缩酶A（ALDOA）是一种关键的糖酵解酶，在多种癌症中高度表达。ALDOA与肺腺癌靶向药物耐药及预后的关系尚不明确。目的　探讨ALDOA在肺腺癌患者靶向药物耐药中的表达及其与患者预后的关系。方法　基于TCGA数据库获取483例肺腺癌组织和59例正常肺组织数据，根据ALDOA表达水平中位值分为高表达组和低表达组（各239例，5例因数据缺失被剔除），评估样本ALDOA表达水平和总生存期之间的关系。纳入2016年10月—2024年5月于新疆医科大学附属肿瘤医院就诊接受埃克替尼靶向治疗后耐药的30例肺腺癌患者，收集患者肿瘤组织活检标本及临床资料。随访时间截至2024-5-30,观察并记录患者疾病稳定（PD）、无进展生存期（PFS）及疾病缓解情况。采用免疫组化法检测标本中ALDOA表达水平，根据ALDOA水平分为高表达组（21例）和低表达组（9例）。分析患者预后情况，采用单因素Cox回归分析肺腺癌患者靶向治疗耐药后PFS影响因素，通过Log-rank检验法进行生存分析比较，采用Kaplan-Meier法绘制PFS生存曲线。结果　基于TCGA数据库分析结果显示，肺腺癌组织中ALDOA表达水平高于正常肺组织（P<0.05），且ALDOA高表达组总生存期（OS）低于低表达组（HR=1.8，P<0.001）；不同临床分期（Ⅰ~Ⅳ期）患者ALDOA表达水平比较，差异有统计学意义（F=5.98，P<0.001）。免疫组化检测结果显示，耐药后肺癌活检组织中ALDOA蛋白表达评分高于耐药前（t配对=4.104，P<0.001）。ALDOA低表达组和高表达组疾病缓解情况比较，ALDOA高表达组ORR低于ALDOA低表达组（P=0.045）；生存分析结果显示，ALDOA低表达组患者的PFS长于高表达组，Log-rank检验结果显示，两组差异有统计学意义（χ2=5.413,P=0.02）。单因素Cox回归分析显示，ALDOA低表达是肺癌靶向耐药后PFS的保护因素（HR=0.066，95%CI=0.007~0.648，P<0.05）；淋巴结转移状态（N2和N3）肺癌靶向耐药后PFS的危险因素（HR=14.015，95%CI=2.017~97.379，P<0.05）。结论　靶向药物治疗后ALDOA表达上调是靶向药耐药的显著特征，其高表达与患者靶向治疗预后不良密切相关。提示ALDOA可能作为预测表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）治疗失败的潜在分子标志物。

关键词: 肺癌, 果糖二磷酸醛缩酶 A, 靶向治疗, 耐药, 预后