Annette Affolter1,2, Marie-France Muller2, Katharina Sommer1, Albrecht Stenzinger1, Karim Zaoui2, Katja Lorenz1, Thomas Wolf1,3, Sarika Sharma2, Janina Wolf1, Sven Perner4, Klaus-Josef Weber5, Kolja Freier6, Peter K Plinkert2, Jochen Hess2,7, Wilko Weichert1,8. 1. Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. 2. Department of Otorhinolaryngology, Head and Neck Surgery, Experimental Head and Neck Oncology, Heidelberg University Hospital, Heidelberg, Germany. 3. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg University Hospital, Heidelberg, Germany. 4. Pathology of the University Hospital of Luebeck and Leibniz Research Center Borstel, Luebeck and Borstel, Germany. 5. Department of Radiation Oncology, Heidelberg, Germany. 6. Department of Oral and Maxillofacial Surgery, Heidelberg University Hospital, Heidelberg, Germany. 7. Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg University Hospital, Heidelberg, Germany. 8. Institute of Pathology, Technical University Munich (TUM), Munich, Germany.
Abstract
BACKGROUND: Despite new radiotherapeutic strategies, radioresistance in head and neck squamous cell carcinoma (HNSCC) remains a major problem. Preclinical model systems are needed to identify resistance mechanisms in this heterogeneous entity. METHODS: We elucidated the interplay among mitogen-activated protein kinase (MAPK)-inhibition, radiation, and p53 mutations in vitro and in a novel ex vivo model derived from vital human HNSCC samples. HNSCC cell lines (p53WT/mut) were treated with the mitogen-activated protein kinase (MEK)-inhibitor PD-0325901 and subsequently irradiated. Radiosensitization was functionally assessed and evaluated in the ex vivo model. RESULTS: We observed a pronounced irradiation-induced extracellular signal-regulated kinase (ERK) phosphorylation in 2 cell lines, which was independent of their p53 mutation status and associated with PD-0325901-related radiosensitization in a clonogenic assay. Heterogeneity in irradiation-induced ERK phosphorylation and in radiosensitization after MEK-inhibition was also reflected in the ex vivo model. CONCLUSION: We provide experimental evidence for radiosensitizing effects of PD-0325901 in HNSCC. The ex vivo culture technology might offer a promising tool for individualized drug efficacy testing.
BACKGROUND: Despite new radiotherapeutic strategies, radioresistance in head and neck squamous cell carcinoma (HNSCC) remains a major problem. Preclinical model systems are needed to identify resistance mechanisms in this heterogeneous entity. METHODS: We elucidated the interplay among mitogen-activated protein kinase (MAPK)-inhibition, radiation, and p53 mutations in vitro and in a novel ex vivo model derived from vital human HNSCC samples. HNSCC cell lines (p53WT/mut) were treated with the mitogen-activated protein kinase (MEK)-inhibitor PD-0325901 and subsequently irradiated. Radiosensitization was functionally assessed and evaluated in the ex vivo model. RESULTS: We observed a pronounced irradiation-induced extracellular signal-regulated kinase (ERK) phosphorylation in 2 cell lines, which was independent of their p53 mutation status and associated with PD-0325901-related radiosensitization in a clonogenic assay. Heterogeneity in irradiation-induced ERK phosphorylation and in radiosensitization after MEK-inhibition was also reflected in the ex vivo model. CONCLUSION: We provide experimental evidence for radiosensitizing effects of PD-0325901 in HNSCC. The ex vivo culture technology might offer a promising tool for individualized drug efficacy testing.
Keywords:
ex vivo model; head and neck cancer; mitogen-activated protein (MAP) kinase signaling pathway; mitogen-activated protein kinase (MEK) inhibitor; p53 mutations; radioresistance
Authors: Jennifer Grünow; Chao Rong; Jan Hischmann; Karim Zaoui; Christa Flechtenmacher; Klaus-Josef Weber; Peter Plinkert; Jochen Hess Journal: J Exp Clin Cancer Res Date: 2017-02-06
Authors: Chao Rong; Marie F Muller; Fang Xiang; Alexandra Jensen; Wilko Weichert; Gerald Major; Peter K Plinkert; Jochen Hess; Annette Affolter Journal: Br J Cancer Date: 2020-05-19 Impact factor: 7.640