Bedeutung einer K-RAS-Mutation für die Strahlensensibilisierung nach EGFR-Blockade

基于第一期资助期的研究结果，重点研究了K-Ras突变对EGR抑制后人类肿瘤细胞放射增敏的作用，延长期的项目计划将重点研究突变型和野生型Ras亚型（K-Ras、H-Ras、NRas）表达谱在erbb介导的头颈部鳞状细胞癌细胞放射耐药和西图昔单抗耐药中的作用。该项目将阐明K-、H-和N-Ras作为erbB受体依赖性信号级联（即PI3K-Akt和Raf-MAPK-Erk）激活介导的放射耐药的生物标志物的作用。关于细胞微环境在体外作用的最新结果，将在2D和3d细胞培养条件下进行分析。在第一期资助期内获得的EGFR抑制后特定HNSCC细胞系体外和体内辐射敏感性的差异结果，将基于基因表达研究来研究细胞和分子生物学背景。此外，在翻译背景下，将详细研究EGFR靶向与顺铂为基础的放化疗联合的重要性和放射生物学疗效。

Based on the results of the first funding period, which were concentrated on the role of K-Ras mutation on radiosensitization of human tumor cells after EGR inhibition, the project planned for the prolongation period will be focused on the role of the expression profile of mutated and wild-type Ras isoforms (K-Ras, H-Ras, NRas) for erbB-mediated radioresistance as well as Cetuximab resistance of head and neck squamous-cell carcinoma cells in vitro. The project will clarify the role of K-, H-, and N-Ras as biomarkers for radioresistance mediated by activation of erbB receptor-dependent signaling cascades, i.e. PI3K-Akt and Raf-MAPK-Erk. With respect to newest results concerning the role of the cellular microenvironment in vitro analyses will be performed under 2D- and 3D-cell culture conditions. The differential results concerning in vitro and in vivo radiation sensitivity of specific HNSCC cell lines after EGFR inhibition, which were obtained in the first funding period, the cell and molecular biological background will be investigated based on gene expression studies. Moreover, in the translational context the importance and radiobiological efficacy of EGFR targeting in combination with cisplatin-based radiochemotherapy will be studied in detail.