Baumann Alexander, Buchberger Anna Maria S, Piontek Guido, Schüttler Dominik, Rudelius Martina, Reiter Rudolf, Gebel Lena, Piendl Gerhard, Brockhoff Gero, Pickhard Anja
Department of Otolaryngology Head and Neck Surgery, Helios Amper-Klinikum Dachau, Dachau, Germany.
Department of Otolaryngology Head and Neck Surgery, Technical University of Munich, Munich, Germany.
Oncotarget. 2018 Jan 30;9(16):12769-12780. doi: 10.18632/oncotarget.24355. eCollection 2018 Feb 27.
Recently the Aurora-Kinases (Aurk) moved into the focus as novel disease related biomarkers and therapeutic targets. Elevated Aurora-Kinase expression has been found in a number of malignancies, amongst them HNSCC. For esophageal cancer, the AurkA Phe31-Ile polymorphism has previously been associated with tumor progression. Here we evaluated the treatment efficiency of HNSCC cell radiation as a function of Aurora-Kinases in HNSCC cell lines. Moreover, we investigated a potential sensitization to radiation by a cell treatment with the inhibitors Alisertib, Barasertib, Docetaxel and VX-680. In parallel the radiation dependent expression and regulation of AurkA/B, p-Akt Ser 473 and Survivin and the AurkA polymorphism were investigated in primary tumor samples. We identified a high-risk collective with elevated AurkA and Survivin or AurkA and p-Akt Ser 473 expression. High AurkA, AurkB, and p-Akt Ser 473 expression was exclusively found in the heterozygous cell line. We found a polymorphism dependent sensitivity to treatments with different Aurk inhibitors: The homozygous cell line UD-SCC-5 could be sensitized to radiation with Docetaxel in combination with any of the Aurora-Kinase inhibitors. In contrast, treatment with Docetaxel or radiation did not enhance the inhibitory effect of Barasertib or VX-680 in the heterozygous SAS cell line. These findings indicate that the Aurora-Kinase A Phe31-Ile-polymorphism is a possibly predictive factor for response to radiation in combination with Docetaxel and Aurora-Kinase inhibitor treatments.
最近，极光激酶（Aurk）作为新型疾病相关生物标志物和治疗靶点受到关注。在许多恶性肿瘤中都发现极光激酶表达升高，其中包括头颈部鳞状细胞癌（HNSCC）。对于食管癌，AurkA Phe31-Ile多态性先前已被证明与肿瘤进展有关。在此，我们评估了HNSCC细胞系中极光激酶对HNSCC细胞放射治疗效果的影响。此外，我们研究了用抑制剂Alisertib、Barasertib、多西他赛和VX-680对细胞进行处理后是否能增强对辐射的敏感性。同时，我们还研究了原发性肿瘤样本中AurkA/B、p-Akt Ser 473和Survivin的辐射依赖性表达及调控以及AurkA多态性。我们确定了一个高危群体，其AurkA和Survivin或AurkA和p-Akt Ser 473表达升高。高AurkA、AurkB和p-Akt Ser 473表达仅在杂合细胞系中发现。我们发现不同Aurk抑制剂治疗存在多态性依赖性敏感性：纯合细胞系UD-SCC-5可通过多西他赛与任何一种极光激酶抑制剂联合使用而对辐射敏感。相比之下，在杂合SAS细胞系中，多西他赛或辐射处理并未增强Barasertib或VX-680的抑制作用。这些发现表明，极光激酶A Phe31-Ile多态性可能是预测多西他赛与极光激酶抑制剂联合放射治疗反应的一个因素。
