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

• Published in: The lancet oncology 2008-03, Vol.9 (3), p.288-296
• Main Authors: Bussink, Johan, Dr, van der Kogel, Albert J, Prof, Kaanders, Johannes HAM, Prof
• Format: Article
• Language: English
• Subjects: Cancer therapies; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - radiotherapy; Cell growth; Cell Hypoxia - radiation effects; Enzyme Activation - radiation effects; Head & neck cancer; Head and Neck Neoplasms - enzymology; Head and Neck Neoplasms - radiotherapy; Hematology, Oncology and Palliative Medicine; Humans; Hypoxia; Kinases; Ligands; Mutation; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol 3-Kinases - radiation effects; Prognosis; Proteins; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-akt - radiation effects; Radiation therapy; Signal transduction; Signal Transduction - physiology; Signal Transduction - radiation effects; Throat cancer; Toxicity; Tumors
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(08)70073-1

Summary 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.