Ceritinib (LDK378) inhibits laryngeal squamous cell carcinoma progression via regulating ROS-induced mitochondrial apoptosis and inducing oxidative stress.

Laryngeal squamous cell carcinoma (LSCC) is a prevalent malignant tumor of the head and neck with unfavorable outcomes. Ceritinib, an FDA-approved tyrosine kinase inhibitor targeting the insulin-like growth factor 1 receptor (IGF1R), has not been thoroughly explored for its therapeutic potential in LSCC. In this study, we demonstrated that Ceritinib significantly inhibits the growth of LSCC cells (TU686 and AMC-HN8), disrupts oxidative stress homeostasis, and induces mitochondrial-mediated apoptosis. Ceritinib triggered ROS overload, and the apoptotic effects were reversed by N-acetylcysteine, confirming ROS-dependent mitochondrial apoptosis. Transcriptome sequencing and Western blot analysis revealed that Ceritinib suppresses PI3K/Akt signaling to promote apoptosis. Ceritinib triggered mitochondria mediated apoptosis via ROS-PI3K/AKT axis to inhibit the progression of LSCC. Furthermore, using Chou-Talalay's method, we calculated the combination index (CI) for Ceritinib and cisplatin, demonstrating that their combination synergistically suppressed the malignant behavior of LSCC cells, exacerbated mitochondrial dysfunction, and enhanced oxidative stress in vitro. In vivo, Ceritinib (25 mg/kg) alone or in combination with cisplatin (2 mg/kg) significantly inhibited LSCC tumor growth without affecting bodyweight. Overall, our findings highlight that Ceritinib, both as a monotherapy and in combination with cisplatin, effectively inhibits LSCC progression in vitro and in vivo-with the combination more potently promoting apoptosis and suppressing tumor cell proliferation, consistent with our in vitro results-underscoring its potential as a promising therapeutic strategy for LSCC treatment.