bay-65-1942 and Squamous-Cell-Carcinoma-of-Head-and-Neck

We explored the role of the transcription factor, NF-κB, and its upstream kinase IKKβ in regulation of migration, invasion, and metastasis of cisplatin-resistant head and neck squamous cell carcinoma (HNSCC). We showed that cisplatin-resistant HNSCC cells have a stronger ability to migrate and invade, as well as display higher IKKβ/NF-κB activity compared to their parental partners. Importantly, we found that knockdown of IKKβ, but not NF-κB, dramatically impaired cell migration and invasion in these cells. Consistent with this, the IKKβ inhibitor, CmpdA, also inhibited cell migration and invasion. Previous studies have already shown that N-Cadherin, an epithelial-mesenchymal transition (EMT) marker, and IL-6, a pro-inflammatory cytokine, play important roles in regulation of HNSCC migration, invasion, and metastasis. We found that cisplatin-resistant HNSCC expressed higher levels of N-Cadherin and IL-6, which were significantly inhibited by CmpdA. More importantly, we showed that CmpdA treatment dramatically abated cisplatin-resistant HNSCC cell metastasis to lungs in a mouse model. Our data demonstrated the crucial role of IKKβ in control of migration, invasion, and metastasis, and implicated that targeting IKKβ may be a potential therapy for cisplatin-resistant metastatic HNSCC.

Topics: Animals; Cell Line, Tumor; Cell Movement; Cisplatin; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Knockdown Techniques; Head and Neck Neoplasms; Humans; I-kappa B Kinase; Lung Neoplasms; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; NF-kappa B; Oxazines; Pyridines; RNA, Small Interfering; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Xenograft Model Antitumor Assays

Epidermal growth factor receptor (EGFR) plays an important role in head and neck squamous cell carcinoma (HNSCC) proliferation and therapy resistance, but the efficacy of targeting of EGFR for therapy has been limited. Here, we explore the molecular link between EGFR and inhibitor of κB kinase β/nuclear factor-κB (IKKβ/NF-κB) signalling pathways in the regulation of HNSCC EGFR inhibitor resistance.. We performed in vitro experiments in eight human HNSCC cell lines and a patient-derived HNSCC cell line as well as in vivo xenografts in a human HNSCC cell line.. We found that treatment of all HNSCC cells with Gefitinib and Erlotinib, two Food Drug Administration-approved EGFR inhibitors, blocked the activity of Akt/mammalian target of the rapamycin (mTOR) and extracellular signal-regulated kinase, two crucial downstream effectors of EGFR, but up-regulated IKKβ/NF-κB signalling. In addition, induction of IKKβ/NF-κB by EGFR inhibitors required HER2 and HER3 expression. In keeping with these, IKKβ inhibitor CmpdA synergistically enhanced the efficacy of EGFR inhibitors to further inhibit in vitro HNSCC cell growth. Importantly, we demonstrated that the combination of Gefitinib with CmpdA inhibited xenograft tumour formation.. Our data demonstrated that co-targeting EGFR and IKKβ with Gefitinib and IKKβ inhibitors could provide a potential novel therapy for head and neck squamous cell cancer.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Gene Expression Regulation, Neoplastic; Humans; I-kappa B Kinase; Mice; NF-kappa B; Oxazines; Protein Kinase Inhibitors; Pyridines; Receptor, ErbB-2; Receptor, ErbB-3; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays