Journal
HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK
Volume 38, Issue -, Pages E2049-E2061Publisher
WILEY
DOI: 10.1002/hed.24376
Keywords
ex vivo model; radioresistance; head and neck cancer; mitogen-activated protein (MAP) kinase signaling pathway; p53 mutations; mitogen-activated protein kinase (MEK) inhibitor
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Funding
- Olympia-Morata-Programme at the Heidelberg University's Medical Faculty
- German Cancer Aid in the framework of the Mildred-Scheel, MD, fellowship program
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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. (C) 2016 Wiley Periodicals, Inc.
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