Elsevier

The Lancet Oncology

Volume 9, Issue 3, March 2008, Pages 288-296
The Lancet Oncology

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

https://doi.org/10.1016/S1470-2045(08)70073-1Get rights and content

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.

Introduction

The treatment of locoregionally advanced squamous-cell carcinoma of the head and neck has developed gradually from surgery to radiotherapy. The major reason for this gradual change in treatment modality is an increased preference for organ preservation strategies. Additionally, the effectiveness of radiotherapy has been improved by approaches that overcome the main mechanisms of radioresistance. Important signal transduction pathways, such as the phosphatidylinositol-3-kinase (PI3-K)/protein kinase B (AKT) cascade, which can be upregulated by radiotherapy, seem to be involved in mechanisms of radiation resistance.1 These pathways offer opportunities to better understand radiation resistance and to further improve the effectiveness of radiotherapy (figure 1). In this review, we discuss the central role of the PI3-K/AKT signal transduction pathway in the three major mechanisms of radioresistance in squamous-cell carcinoma of the head and neck: tumour-cell proliferation; hypoxia; and intrinsic radioresistance.

Section snippets

Strategies for increasing radiosensitivity

A change in the fractionation schedules of radiotherapy is a classic example of a modified treatment for overcoming resistance to radiotherapy. By delivering a higher dose of radiation to the tumour than conventional radiotherapy, hyperfractionation aims to overcome intrinsic radioresistance, whereas accelerated fractionation aims to counteract compensatory tumour-cell repopulation by reducing the overall treatment time. Randomised trials and a meta-analysis have shown that both strategies are

PI3-K/AKT pathway

PI3-K/AKT is one of the major downstream targets of the ERBB tyrosine-kinase receptor family (figure 1). The four closely related members of this family, ERBB1 (EGFR), ERBB2, ERBB3, and ERBB4, are activated by ligand-induced receptor homodimerisation and heterodimerisation. ERBB2 and ERBB3 are non-autonomous: ERBB2 does not have the capacity to interact with a growth-factor ligand and the kinase activity of ERBB3 is defective.8 On heterodimerisation of the receptor, the cytoplasmic domain of

PI3-K/AKT pathway and radioresistance

The PI3-K/AKT pathway regulates various cellular functions, several of which are involved in the most important mechanisms of radioresistance: intrinsic radioresistance; tumour-cell proliferation; and hypoxia.

EGFR and PI3-K/AKT activation

High EGFR expression is strongly correlated with worse disease-free survival in head and neck cancer than that associated with low EGFR expression and has been shown to be a better predictor for relapse than tumour stage.62 Although EGFR overexpression is present in at least 80% of head and neck squamous-cell carcinomas,35, 36, 63 only a few of these tumours show a clinically meaningful response to EGFR inhibition. In one study, treatment with cetuximab in patients with recurrent and

Conclusion

This review clearly shows that the PI3-K/AKT pathway is implicated in all major mechanisms of radioresistance. Additionally, EGFR-independent activation of the PI3-K/AKT pathway commonly occurs and is of clinical relevance. Retrospective studies have shown that pAKT expression is an independent prognostic factor for outcome in patients with head and neck cancers. The blocking of PI3-K/AKT signalling routes via EGFR inhibition can improve radiosensitivity and can affect tumour growth

Search strategy and selection criteria

Data for this review were identified by a Medline search using PubMed and references from relevant articles using the search terms “head and neck cancer”, “AKT”, “PI3-K”, “hypoxia”, “radiosensitivity”, “proliferation”, and “EGFR”. Abstracts and reports from meetings were included only when they related directly to previously published work. Only papers published in English between January, 1997, and September, 2007, were used.

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