title: Targeting EGFR-PI3K-AKT-mTOR signaling enhances radiosensitivity in head and neck squamous cell carcinoma.
abstract: BACKGROUND
  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.
  
  
  METHODS
  This review covers EGFR-phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-mechanistic target of rapamycin (mTOR) signaling in HNSCC. The role of each pathway node in radioresistance is discussed. Preclinical and clinical innovative aspects of targeting EGFR-PI3K-AKT and mTOR are demonstrated. Ongoing clinical trials and future perspectives are presented.
  
  
  CONCLUSIONS
  Different cellular signaling pathways seem to mediate radioresistance in advanced HNSCC and various molecular targeted therapies are currently being investigated to sensitize tumor cells to radiotherapy. Recently, new insights in the mutational landscape of HNSCC unraveled critical alterations in putative oncogenes and tumor suppressor genes and have emphasized the importance of PI3K and the corresponding upstream and downstream signaling pathways in pathogenesis and treatment response. The frequent activation of the EGFR-PI3K-AKT-mTOR pathway in HNSCC and its implication in the context of radiosensitivity make this pathway one of the most promising targets in the therapy of HNSCC patients. Clinical studies targeting EGFR and mTOR in combination with radiotherapy are under investigation.
authors: University Hospital Heidelberg, Department of Oral and Maxillofacial Surgery , Im Neuenheimer Feld 400, 69120 Heidelberg , Germany +49 0 6221 56 38462 ; +49 0 6221 56 4222 ; chr.freudlsperger@med.uni-heidelberg.de.
authors: Dominik
authors: D
authors: Horn
authors: Jochen
authors: J
authors: Hess
authors: Kolja
authors: K
authors: Freier
authors: Jürgen
authors: J
authors: Hoffmann
authors: Christian
authors: C
authors: Freudlsperger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000628:therapy*; D006801:Humans; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000502:physiology; D000077195:Squamous Cell Carcinoma of Head and Neck; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: head and neck squamous cell carcinoma; mechanistic target of rapamycin; phosphoinositide 3-kinase; proteinkinase B; radiotherapy