Ceritinib Reduces Transendothelial Invasion of Non-small Cell Lung Cancer Cells by Restoring Claudin-10 and Suppressing VEGF-A Signaling

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.

BBB; Brain metastases; Ceritinib; Claudin-10; NSCLC.