Targeting irradiation‐induced mitogen‐activated protein kinase activation in vitro and in an ex vivo model for human head and neck cancer. (26th February 2016)

• Record Type: Journal Article
• Authors: Affolter, Annette; Muller, Marie‐France; Sommer, Katharina; Stenzinger, Albrecht; Zaoui, Karim; Lorenz, Katja; Wolf, Thomas; Sharma, Sarika; Wolf, Janina; Perner, Sven; Weber, Klaus‐Josef; Freier, Kolja; Plinkert, Peter K.; Hess, Jochen; Weichert, Wilko
• Is Part Of: Head & neck. Volume 38(2016)Supplement 1
• Page Start: E2049
• Page End: E2061
• Publication Date: 2016-02-26
• Subjects: ex vivo model -- radioresistance -- head and neck cancer -- mitogen‐activated protein (MAP) kinase signaling pathway -- p53 mutations -- mitogen‐activated protein kinase (MEK) inhibitor; Head -- Diseases -- Periodicals; Neck -- Diseases -- Periodicals; Head -- Periodicals; Neck -- Periodicals; Face -- Periodicals; 617.51059
• DOI: 10.1002/hed.24376
• Languages: English
• ISSNs: 1043-3074

Abstract

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. © 2016 Wiley Periodicals, Inc. Head Neck 38 : E2049–E2061, 2016