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
Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Department of Otorhinolaryngology, Head and Neck Surgery, Experimental Head and Neck Oncology, Heidelberg University Hospital, Heidelberg, Germany.
Head Neck. 2016 Apr;38 Suppl 1:E2049-61. doi: 10.1002/hed.24376. Epub 2016 Feb 26.
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.
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.
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.
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.
尽管有新的放射治疗策略，但头颈部鳞状细胞癌（HNSCC）的放射抗性仍然是一个主要问题。需要临床前模型系统来确定这种异质性实体中的抗性机制。
我们在体外以及源自活体人类HNSCC样本的新型离体模型中阐明了丝裂原活化蛋白激酶（MAPK）抑制、辐射和p53突变之间的相互作用。用丝裂原活化蛋白激酶（MEK）抑制剂PD - 0325901处理HNSCC细胞系（p53野生型/突变型），随后进行照射。在离体模型中对放射增敏作用进行功能评估和评价。
我们在2种细胞系中观察到明显的辐射诱导的细胞外信号调节激酶（ERK）磷酸化，这与它们的p53突变状态无关，并且在克隆形成试验中与PD - 0325901相关的放射增敏作用有关。离体模型也反映了辐射诱导的ERK磷酸化和MEK抑制后放射增敏的异质性。
我们提供了PD - 0325901对HNSCC有放射增敏作用的实验证据。离体培养技术可能为个体化药物疗效测试提供一个有前景的工具。©2016威利期刊公司。头颈外科38：E2049 - E2061，2016年。
