Targeting <scp>TGF</scp> beta receptor 1 in head and neck squamous cell carcinoma
Bernhard J. Jank, Julia Schnoell, Katharina Kladnik, Carmen Sparr, Markus Haas, Elisabeth Gurnhofer, Alexander Lein, Markus Brunner, Lukas Kenner, Lorenz Kadletz‐Wanke, Gregor Heiduschka
Abstract
Abstract Objectives The transforming growth factor‐Beta (TGF‐ß) pathway may be involved in the radioresistance of head and neck squamous cell carcinoma (HNSCC). This study analyzed TGF‐ß receptor 1 (TGFBR1) expression in HNSCC patients and evaluated the antineoplastic and radiosensitizing effects of vactosertib, a novel TGFBR1 inhibitor, in vitro. Materials and Methods TGFBR1 expression was examined in HNSCC patients at the mRNA level in silico and the protein level by immunohistochemistry, including surgical specimens of primary tumors, matched lymph node metastasis, and recurrent disease. Furthermore, a novel small molecule TGFBR1 inhibitor was evaluated in HNSCC cell lines. Finally, an indirect coculture model using patient‐derived cancer‐associated fibroblasts was applied to mimic the tumor microenvironment. Results Patients with high TGFBR1 mRNA levels showed significantly worse overall survival in silico (OS, p = 0.024). At the protein level, an association between TGFBR1 + tumor and OS was observed for the subgroup with TGFBR1‐stroma ( p = 0.001). Those results prevailed in multivariable analysis. Inhibition of TGFBR1 showed antineoplastic effects in vitro. In combination with radiation, vactosertib showed synergistic effects. Conclusion Our results indicate a high risk of death in tumor TGFBR1+ | stroma TGFBR1‐ expressing patients. In vitro data suggest a potential radiosensitizing effect of TGFBR1 inhibition by vactosertib.