The Aurora-Kinase A Phe31-Ile polymorphism as possible predictor of response to treatment in head and neck squamous cell carcinoma.

Alexander Baumann,Dominik Schüttler,Anna Maria S Buchberger,Guido Piontek,Anja Pickhard,Gero Brockhoff,Martina Rudelius,Rudolf Reiter,Gerhard Piendl,Lena Gebel

doi:10.18632/oncotarget.24355

Abstract

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.

Highlights

The median 5-year survival for patients with head and neck squamous cell carcinoma (HNSCC) is 50% [1] and at least 50% of patients with a stage III disease relapse in the first two years after therapy [2]
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
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

Summary

Introduction

The median 5-year survival for patients with head and neck squamous cell carcinoma (HNSCC) is 50% [1] and at least 50% of patients with a stage III disease relapse in the first two years after therapy [2]. These facts reflect the very poor prognosis for patients with HNSCC. First attempts of HNSCC therapy in the early twentieth century pursued an anatomical approach based on surgical resection and radiotherapy. Targeting the epidermal growth factor receptor (EGFR) with cetuximab (Erbitux®) has been established and complements standard approaches. It has been shown that EGFR targeting significantly improves the overall survival (OS) of HNSCC patients [1]

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Results

Conclusion