Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer

Lancet Oncol. 2008 Mar;9(3):288-96. doi: 10.1016/S1470-2045(08)70073-1.


Activation of the phosphatidylinositol-3-kinase (PI3-K)/protein kinase B (AKT) pathway is associated with three major radioresistance mechanisms: intrinsic radioresistance; tumour-cell proliferation; and hypoxia. Monitoring and manipulation of this signal-transduction pathway can have important implications for the management of head and neck cancer, because activation of the PI3-K/AKT pathway is a frequent event in these tumours. PI3-K/AKT signalling regulates cellular processes, including proliferation, invasion, apoptosis, and the upregulation of hypoxia-related proteins. Activation of this pathway can be caused by stimulation of receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR). In clinical trials, a strong and independent association has been noted between expression of activated AKT and treatment outcome. Therefore, the search for molecular predictors of sensitivity to EGFR-directed treatment should be extended to markers of PI3-K/AKT activation. Another strategy might be the direct targeting and inhibition of this pathway. Such inhibition will enhance the efficacy of radiotherapy, by antagonising radiation-induced cellular defense mechanisms, especially in tumours that have activated the PI3-K/AKT cascade. Thus, the activation status of this pathway might be a key element for the prediction of treatment response and for therapeutic targeting in head and neck cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Carcinoma, Squamous Cell / enzymology*
  • Carcinoma, Squamous Cell / radiotherapy
  • Cell Hypoxia / radiation effects
  • Enzyme Activation / radiation effects
  • Head and Neck Neoplasms / enzymology*
  • Head and Neck Neoplasms / radiotherapy
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / radiation effects*
  • Phosphoinositide-3 Kinase Inhibitors
  • Prognosis
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-akt / radiation effects*
  • Signal Transduction / physiology
  • Signal Transduction / radiation effects*


  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt