Phosphorylation of AKT(Ser473) serves as an independent prognostic marker for radiosensitivity in advanced head and neck squamous cell carcinoma
Corresponding Author
Christian Freudlsperger
Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Germany
C. F., D. H., K. F. and J. H. contributed equally to this work
Correspondence to: Dr. med. Dr. med. dent. Christian Freudlsperger, Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany, Tel.: +49 (0)6221 56 38462, Fax: +49 (0) 6221 56 4222, E-mail: [email protected]Search for more papers by this authorDominik Horn
Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Germany
C. F., D. H., K. F. and J. H. contributed equally to this work
Search for more papers by this authorSebastian Weißfuß
Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorWilko Weichert
Institute of Pathology, University Hospital Heidelberg, Germany
Search for more papers by this authorKlaus-Josef Weber
Department of Radiation Oncology, University of Heidelberg, Germany
Search for more papers by this authorDaniel Saure
Institute of Medical Biometry and Informatics, University of Heidelberg, Germany
Search for more papers by this authorSarika Sharma
Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorGerhard Dyckhoff
Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorNiels Grabe
Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, Heidelberg, Germany
Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany
Search for more papers by this authorPeter Plinkert
Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorJürgen Hoffmann
Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Germany
Search for more papers by this authorKolja Freier
Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Germany
C. F., D. H., K. F. and J. H. contributed equally to this work
Search for more papers by this authorJochen Hess
Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany
C. F., D. H., K. F. and J. H. contributed equally to this work
Search for more papers by this authorCorresponding Author
Christian Freudlsperger
Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Germany
C. F., D. H., K. F. and J. H. contributed equally to this work
Correspondence to: Dr. med. Dr. med. dent. Christian Freudlsperger, Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany, Tel.: +49 (0)6221 56 38462, Fax: +49 (0) 6221 56 4222, E-mail: [email protected]Search for more papers by this authorDominik Horn
Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Germany
C. F., D. H., K. F. and J. H. contributed equally to this work
Search for more papers by this authorSebastian Weißfuß
Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorWilko Weichert
Institute of Pathology, University Hospital Heidelberg, Germany
Search for more papers by this authorKlaus-Josef Weber
Department of Radiation Oncology, University of Heidelberg, Germany
Search for more papers by this authorDaniel Saure
Institute of Medical Biometry and Informatics, University of Heidelberg, Germany
Search for more papers by this authorSarika Sharma
Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorGerhard Dyckhoff
Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorNiels Grabe
Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, Heidelberg, Germany
Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany
Search for more papers by this authorPeter Plinkert
Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorJürgen Hoffmann
Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Germany
Search for more papers by this authorKolja Freier
Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Germany
C. F., D. H., K. F. and J. H. contributed equally to this work
Search for more papers by this authorJochen Hess
Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany
C. F., D. H., K. F. and J. H. contributed equally to this work
Search for more papers by this authorConflicts of Interest: The authors declare no conflicts of interest to disclose.
Abstract
Head and neck squamous cell carcinoma (HNSCC) is frequently characterized by high resistance to radiotherapy, which critically depends on both altered signaling pathways within tumor cells and their dynamic interaction with the tumor microenvironment. This study evaluated the prognostic value of the phosphorylation status of AKT on Ser473 and Thr308 for the clinical outcome of patients with advanced HNSCC on radiotherapy. Furthermore, we investigated the impact of AKT(Ser473) phosphorylation [p-AKT(Ser473)] in the context of radioresistance using ex vivo tissue cultures that resemble the complex tissue architecture and paracrine interaction with the tumor microenvironment. In a cohort of 120 patients with advanced HNSCC, who were treated with primary or adjuvant radiotherapy, a significant association was found between relative p-AKT(Ser473) levels and overall survival (p = 0.006) as well as progression-free survival (p = 0.021), while no significant correlation was revealed for relative p-AKT(Thr308) levels. In ex vivo tissue cultures p-AKT(Ser473) levels were increased upon irradiation and treatment with the PI3K inhibitor LY294002 inhibited both basal and irradiation induced AKT(Ser473) phosphorylation. Strikingly, pretreatment with LY294002 sensitized tissue cultures derived from primary and recurrent tumors to radiotherapy as determined by impaired tumor cell proliferation and enhanced DNA damage. In conclusion, phosphorylation status of AKT(Ser473) in tumor specimens serves as a novel biomarker to identify patients with advanced HNSCC at high risk for treatment failure following radiotherapy, and our data from ex vivo tissue cultures support the assumption that pharmacological inhibition of AKT(Ser473) phosphorylation might circumvent radioresistance to improve efficiency and reduce toxicity of current treatment modalities.
Abstract
What's new?
Patients with head and neck squamous cell cancers often develop resistance to radiotherapy. To figure out how, these authors investigated AKT phosphorylation in the tumor cells. AKT kinase boosts cell proliferation when it is activated by phosphorylation at two possible sites. Could the location of phosphorylation predict whether the tumor will develop resistance? These results suggest it could. The authors show that patients with more phosphorylation at serine 473 had worse survival; furthermore, they showed that reducing phosphorylation at this site increased cancer cells' vulnerability to irradiation. Phosphorylation at the other site, threonine 308, did not affect survival.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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