Receptor tyrosine kinase MET as potential target of multi‐kinase inhibitor and radiosensitizer sorafenib in HNSCC

• DOI: 10.1002/hed.25440
• Publication Date: 2018-12-15T15:54:55Z
• Authors: Kaweh Beizaei; Lisa Gleißner; Konstantin Hoffer; Lara Bußmann; Anh Thu Vu; Leonhard Steinmei...; Simon Laban; Nikolaus Möckelmann; Adrian Münscher; Cordula Petersen; Kai Rothkamm; Malte Kriegs
• Keywords: Sulfonamides; Indoles; Cell Survival; Proto-Oncogene Proteins c-met; Sorafenib; Piperazines; 3. Good health; ErbB Receptors; 03 medical and health sciences; 0302 clinical medicine; Crizotinib; Head and Neck Neoplasms; Cell Line, Tumor; Carcinoma, Squamous Cell; Humans; Phosphorylation; Protein Kinase Inhibitors; Cell Proliferation

AbstractBackgroundThe multi‐kinase inhibitor sorafenib displays antitumoral effects in head and neck squamous cell carcinoma (HNSCC); however, the targeted kinases are unknown. Here we aimed to identify those kinases to determine the mechanism of sorafenib‐mediated effects and establish candidate biomarkers for patient stratification.MethodsThe effects of sorafenib and MET inhibitors crizotinib and SU11274 were analyzed using a slide‐based antibody array, Western blotting, proliferation, and survival assays. X‐rays were used for irradiations.ResultsSorafenib inhibited auto‐phosphorylation of epidermal growth factor receptor and MET, which has not been described previously. MET expression in HNSCC cells was not always associated with activity/phosphorylation. Furthermore, sorafenib‐dependent cell kill and radiosensitization was not associated with MET level. Although MET inhibitors blocked proliferation, they caused only mild cytotoxicity and no radiosensitization.ConclusionWe identified MET as a new potential target of sorafenib. However, MET inhibition is not the cause for sorafenib‐mediated cytotoxicity or radiosensitization.