Abstract：
OBJECTIVE: Epidermal growth factor receptor (EGFR) mutation is a prominent driver of lung cancer. Tyrosine kinase inhibitors (TKIs) have shown efficacy in treating EGFR-mutant lung cancer, but the emergence of drug resistance poses a significant challenge. Recent research has highlighted solute carrier family 12 member 8 (SLC12A8) as one of the highly upregulated genes in various cancer types. However, its oncogenic function remains largely unexplored.
METHODS: 343 consecutive lung cancer patients were prospectively recruited and were followed for over 10 years. SLC12A8 expression in lung cancer tissues was measured by qPCR and was associated with patient survival. The association of SLC12A8 with TKI resistance was studied in in vitro EGFR-mutant lung cancer cell line as well as in in vivo xenograft tumor model. High-throughput kinome screening was employed to investigate SLC12A8-mediated oncogenic signaling pathway in lung cancer.
RESULTS: SLC12A8 is a predictive biomarker of poor prognosis in lung cancer, particularly in patients with EGFR mutations. SLC12A8 overexpression diminishes the effectiveness of TKIs in EGFR-mutant lung cancer, resulting in treatment failure and disease progression. More importantly, SLC12A8-induced TKI resistance is mediated by the PDK1/AKT signaling axis, while silencing SLC12A8 expression inhibits oncogenic PDK1/AKT signaling, restoring TKI sensitivity in lung cancer cells.
CONCLUSIONS: SLC12A8 mediates TKI resistance in EGFR-mutant lung cancer via PDK1/AKT axis. These findings not only advance our understanding of the molecular mechanisms driving TKI resistance, but also offer novel alternative strategies for the treatment of lung cancer.
METHODS: 343 consecutive lung cancer patients were prospectively recruited and were followed for over 10 years. SLC12A8 expression in lung cancer tissues was measured by qPCR and was associated with patient survival. The association of SLC12A8 with TKI resistance was studied in in vitro EGFR-mutant lung cancer cell line as well as in in vivo xenograft tumor model. High-throughput kinome screening was employed to investigate SLC12A8-mediated oncogenic signaling pathway in lung cancer.
RESULTS: SLC12A8 is a predictive biomarker of poor prognosis in lung cancer, particularly in patients with EGFR mutations. SLC12A8 overexpression diminishes the effectiveness of TKIs in EGFR-mutant lung cancer, resulting in treatment failure and disease progression. More importantly, SLC12A8-induced TKI resistance is mediated by the PDK1/AKT signaling axis, while silencing SLC12A8 expression inhibits oncogenic PDK1/AKT signaling, restoring TKI sensitivity in lung cancer cells.
CONCLUSIONS: SLC12A8 mediates TKI resistance in EGFR-mutant lung cancer via PDK1/AKT axis. These findings not only advance our understanding of the molecular mechanisms driving TKI resistance, but also offer novel alternative strategies for the treatment of lung cancer.
摘要：
目的：表皮生长因子受体（EGFR）突变是肺癌的主要驱动因素。酪氨酸激酶抑制剂（TKIs）已显示出治疗EGFR突变肺癌的疗效，但是耐药性的出现带来了巨大的挑战。最近的研究强调溶质载体家族12成员8（SLC12A8）是各种癌症类型中高度上调的基因之一。然而,其致癌功能在很大程度上仍未被探索。
方法：前瞻性招募343名连续肺癌患者，并随访10年以上。通过qPCR测量肺癌组织中的SLC12A8表达，并与患者生存率相关。在体外EGFR突变肺癌细胞系以及体内异种移植肿瘤模型中研究了SLC12A8与TKI抗性的关联。高通量kinome筛选用于研究SLC12A8介导的肺癌致癌信号通路。
结果：SLC12A8是肺癌预后不良的预测生物标志物，特别是EGFR突变患者。SLC12A8过表达降低了TKIs在EGFR突变肺癌中的有效性，导致治疗失败和疾病进展。更重要的是,SLC12A8诱导的TKI抗性由PDK1/AKT信号轴介导，而沉默SLC12A8表达抑制致癌PDK1/AKT信号，恢复肺癌细胞的TKI敏感性。
结论：SLC12A8通过PDK1/AKT轴介导EGFR突变型肺癌的TKI耐药。这些发现不仅促进了我们对驱动TKI抗性的分子机制的理解，同时也为肺癌的治疗提供了新的替代策略。
方法：前瞻性招募343名连续肺癌患者，并随访10年以上。通过qPCR测量肺癌组织中的SLC12A8表达，并与患者生存率相关。在体外EGFR突变肺癌细胞系以及体内异种移植肿瘤模型中研究了SLC12A8与TKI抗性的关联。高通量kinome筛选用于研究SLC12A8介导的肺癌致癌信号通路。
结果：SLC12A8是肺癌预后不良的预测生物标志物，特别是EGFR突变患者。SLC12A8过表达降低了TKIs在EGFR突变肺癌中的有效性，导致治疗失败和疾病进展。更重要的是,SLC12A8诱导的TKI抗性由PDK1/AKT信号轴介导，而沉默SLC12A8表达抑制致癌PDK1/AKT信号，恢复肺癌细胞的TKI敏感性。
结论：SLC12A8通过PDK1/AKT轴介导EGFR突变型肺癌的TKI耐药。这些发现不仅促进了我们对驱动TKI抗性的分子机制的理解，同时也为肺癌的治疗提供了新的替代策略。
