Targeting TGF beta receptor 1 in head and neck squamous cell carcinoma

Bernhard J Jank; Julia Schnoell; Katharina Kladnik; Carmen Sparr; Markus Haas; Elisabeth Gurnhofer; Alexander L Lein; Markus Brunner; Lukas Kenner; Lorenz Kadletz-Wanke; Gregor Heiduschka

doi:10.1111/odi.14594

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Title (eng)

Targeting TGF beta receptor 1 in head and neck squamous cell carcinoma

Author

Bernhard J Jank

Julia Schnoell

Katharina Kladnik

Carmen Sparr

Markus Haas

Elisabeth Gurnhofer

Alexander L Lein

Markus Brunner

Lukas Kenner

University of Veterinary Medicine Vienna

Lorenz Kadletz-Wanke

Gregor Heiduschka

Abstract (eng)

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.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.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.Our results indicate a high risk of death in tumorTGFBR1+|stromaTGFBR1- expressing patients. In vitro data suggest a potential radiosensitizing effect of TGFBR1 inhibition by vactosertib.

Keywords (eng)

HumansReceptor, Transforming Growth Factor-beta Type I MetabolismReceptor, Transforming Growth Factor-beta Type I Antagonists & InhibitorsSquamous Cell Carcinoma of Head and Neck MetabolismSquamous Cell Carcinoma of Head and Neck GeneticsSquamous Cell Carcinoma of Head and Neck PathologyHead and Neck Neoplasms MetabolismHead and Neck Neoplasms GeneticsMaleFemaleCell Line, TumorMiddle AgedAgedTumor MicroenvironmentRadiation-Sensitizing Agents PharmacologyRadiation-Sensitizing Agents Therapeutic UseRNA, Messenger MetabolismCancer-Associated Fibroblasts MetabolismCancer-Associated Fibroblasts Drug EffectsAntineoplastic Agents PharmacologyAntineoplastic Agents Therapeutic UseAniline CompoundsTriazoles

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4246

DOI

10.1111/odi.14594

Is in series

Title (eng)

Oral Diseases

Volume