Targeting EGFR-PI3K-AKT-mTOR signaling enhances radiosensitivity in head and neck squamous cell carcinoma

Expert Opin Ther Targets. 2015 Jun;19(6):795-805. doi: 10.1517/14728222.2015.1012157. Epub 2015 Feb 5.

Abstract

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.

Keywords: head and neck squamous cell carcinoma; mechanistic target of rapamycin; phosphoinositide 3-kinase; proteinkinase B; radiotherapy.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / therapy*
  • Combined Modality Therapy
  • ErbB Receptors / metabolism
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / therapy*
  • Humans
  • Molecular Targeted Therapy*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Radiation Tolerance
  • Signal Transduction / physiology
  • Squamous Cell Carcinoma of Head and Neck
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Microenvironment / physiology

Substances

  • Antineoplastic Agents
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases