Xu Xin, Yang Guiwen, Shi Nan
Department of Respiratory Medicine, No.964 Hospital of People's Liberation Army, No.4799 Xi'an Road, Changchun, Jilin, 130062, China.
Biochem Genet. 2025 Apr 21. doi: 10.1007/s10528-025-11103-5.
Non-small cell lung cancer (NSCLC) cells that cross the blood-brain barrier (BBB) can lead to brain metastases, a severe complication of NSCLC. 7Preventing brain metastasis is crucial for improving the survival rates of NSCLC patients. Ceritinib, a tyrosine kinase inhibitor, is approved for treating certain advanced stages of NSCLC. This study investigates the potential of ceritinib in blocking brain metastasis by examining its effect on NSCLC cell transendothelial invasion using an in vitro BBB model. Our findings demonstrate that co-culturing human brain microvascular endothelial cells (hCMEC/D3) with NSCLC lines A549, NCI-H292, and NCI-H596 increases paracellular permeability and reduces transendothelial electrical resistance. Ceritinib mitigates these effects, preventing NSCLC cell invasion through the hCMEC/D3 monolayer and restoring Claudin-10 expression in hCMEC/D3 cells. Knocking down Claudin-10 counteracts the beneficial effects of ceritinib in reducing endothelial permeability. Mechanistically, ceritinib suppresses the expression of VEGF-A and VEGF-R2. Adding VEGF-A reverses ceritinib's protective effect against NSCLC cell invasion. Our results indicate that ceritinib may diminish NSCLC-caused BBB compromise by restoring Claudin-10-associated tight junctions, potentially by influencing VEGF-A/VEGF-R2 signaling. More research is needed to clarify how ceritinib specifically interacts with and regulates the VEGF pathway.
穿过血脑屏障（BBB）的非小细胞肺癌（NSCLC）细胞可导致脑转移，这是NSCLC的一种严重并发症。预防脑转移对于提高NSCLC患者的生存率至关重要。色瑞替尼是一种酪氨酸激酶抑制剂，已被批准用于治疗某些晚期NSCLC。本研究通过使用体外血脑屏障模型检测色瑞替尼对NSCLC细胞跨内皮侵袭的影响，来研究其阻断脑转移的潜力。我们的研究结果表明，将人脑微血管内皮细胞（hCMEC/D3）与NSCLC细胞系A549、NCI-H292和NCI-H596共培养会增加细胞旁通透性并降低跨内皮电阻。色瑞替尼可减轻这些影响，防止NSCLC细胞穿过hCMEC/D3单层，并恢复hCMEC/D3细胞中Claudin-10的表达。敲低Claudin-10可抵消色瑞替尼在降低内皮通透性方面的有益作用。从机制上讲，色瑞替尼会抑制VEGF-A和VEGF-R2的表达。添加VEGF-A可逆转色瑞替尼对NSCLC细胞侵袭的保护作用。我们的结果表明，色瑞替尼可能通过恢复与Claudin-10相关的紧密连接来减轻NSCLC引起的血脑屏障损伤，这可能是通过影响VEGF-A/VEGF-R2信号传导实现的。需要更多的研究来阐明色瑞替尼如何具体与VEGF途径相互作用并对其进行调节。
