Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer.
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.
Bussink
Johan
J
Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Netherlands. j.bussink@rther.umcn.nl
van der Kogel
Albert J
AJ
Kaanders
Johannes H A M
JH
D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000532:radiotherapy; D015687:Cell Hypoxia / Q000528:radiation effects; D004789:Enzyme Activation / Q000528:radiation effects; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000532:radiotherapy; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000528:radiation effects*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000528:radiation effects*; D015398:Signal Transduction / Q000502:physiology / Q000528:radiation effects*
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt