NF-κB/ALDH1A1 信号通路激活促进非小细胞肺癌对 EGFR-TKI 的非突变型耐药
Activation of the NF-κB/ALDH1A1 signaling promotes non-mutational resistance to EGFR-TKIs in non-small cell lung cancer.
作者
作者单位
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
- College of Chemistry, Fuzhou University, 2 Xueyuan Road, Fuzhou, 350116, China.
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China. linwansong@fjzlhospital.com.
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, 350004, China. dalizheng@fjmu.edu.cn.
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China. zjyunbin@fjmu.edu.cn.
摘要
中文
在 EGFR 突变型非小细胞肺癌（NSCLC）治疗中，酪氨酸激酶抑制剂（TKI）的获得性耐药仍是重大临床挑战。本研究通过整合细胞系、肺癌类器官（LCOs）及体内模型建立 TKI 耐药变体，揭示了 NF-κB/ALDH1A1 信号通路在介导非突变型 TKI 耐药中的关键作用。耐药细胞表现出升高的 RELA 磷酸化水平、增强的 ALDH1A1 表达及酶活性，以及干细胞样特征。机制上，NF-κB 激活作为 TKI 暴露的早期反应，并通过 RELA 促进 ALDH1A1 转录；反过来，ALDH1A1 又维持 NF-κB 信号通路的持续激活，形成自我增强的正反馈环。遗传性沉默 ALDH1A1 或 RELA 可逆转耐药表型。在药物层面，EGFR-TKI 联用 ALDH1A1 抑制剂双硫仑（disulfiram）或 NF-κB 靶向药物 EGCG 在体外和体内均可协同恢复 TKI 的抗肿瘤疗效。这些发现确立了 NF-κB/ALDH1A1 信号通路作为获得性 EGFR-TKI 耐药的关键非遗传学机制，并提供了合理的联合策略以克服耐药。催化依赖性 NF-κB–ALDH1A1 反馈环驱动非突变型 EGFR-TKI 耐药。EGFR-TKI 治疗抑制 EGFR 信号通路，但在 EGFR 突变型 NSCLC 细胞中迅速诱导 NF-κB 激活作为 TKI 应激下的早期事件。活化的 NF-κB（p-RELA）驱动 ALDH1A1 转录，而 ALDH1A1 的酶活性通过 IKKβ 磷酸化进一步强化 NF-κB 信号通路，形成催化依赖性正反馈环以维持干性并促进非突变型 TKI 耐药。通过抑制 ALDH1A1（DSF）或 NF-κB（EGCG）破坏该轴可恢复 TKI 敏感性。
English
Acquired resistance to tyrosine kinase inhibitors (TKIs) remains a major clinical challenge in the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). This study established TKI-resistant variants by integrating cell lines, lung cancer organoids (LCOs), and in vivo models, revealing the pivotal role of the NF-κB/ALDH1A1 signaling in mediating non-mutational TKI resistance. Resistant cells exhibited elevated RELA phosphorylation, enhanced ALDH1A1 expression and enzymatic activity, and stem-like properties. Mechanistically, NF-κB activation occurred as an early response to TKI exposure and promoted ALDH1A1 transcription via RELA. In turn, ALDH1A1 contributed to the sustained activation of NF-κB signaling, forming a self-reinforcing positive feedback loop. Genetic ALDH1A1 or RELA silencing reversed the resistant phenotype. Pharmacologically, treatment with an EGFR-TKI and the ALDH1A1 inhibitor disulfiram or the NF-κB-targeting agent EGCG synergistically restored the antitumor efficacy of TKIs both in vitro and in vivo. These findings establish the NF-κB/ALDH1A1 signaling as a key non-genetic mechanism of acquired EGFR-TKI resistance and provide a rational combination strategy to overcome it. Catalysis-dependent NF-κB-ALDH1A1 feedback loop drives non-mutational EGFR-TKI resistance. EGFR-TKI treatment suppresses EGFR signaling but rapidly induces NF-κB activation as an early event under TKI stress in EGFR-mutant NSCLC cells. Activated NF-κB (p-RELA) drives ALDH1A1 transcription, while ALDH1A1 enzymatic activity reinforces NF-κB signaling via IKKβ phosphorylation, forming a catalysis-dependent positive feedback loop that sustains stemness and promotes non-mutational TKI resistance. Disruption of this axis by inhibiting ALDH1A1 (DSF) or NF-κB (EGCG) restores TKI sensitivity.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 9.1
- 新锐分区
- 1区