Clinical update on cancer: molecular oncology of head and neck cancer

Abstract

Head and neck cancers encompass a heterogeneous group of tumours that, in general, are biologically aggressive in nature. These cancers remain difficult to treat and treatment can cause severe, long-term side effects. For patients who are not cured by surgery and/or (chemo)radiotherapy, there are few effective treatment options. Targeted therapies and predictive biomarkers are urgently needed in order to improve the management and minimise the treatment toxicity, and to allow selection of patients who are likely to benefit from both nonselective and targeted therapies. This clinical update aims to provide an insight into the current understanding of the molecular pathogenesis of the disease, and explores the novel therapies under development and in clinical trials.

Figure 1

The p53 structure with different protein domains (transactivation domain, proline-rich domain, DNA-binding domain, oligomerisation domain and regulation domain). Vertical lines indicate the occurrence of mutation of the amino acid residues in HNSCC (data from COSMIC website: cancer.sanger.ac.uk/cancergenome/projects/cosmic)

Figure 2

Schematic representation of the major molecular pathways affected in HNSCC. Stars indicate possible mutations in the molecule. EGFR, MET and NOTCH activation can promote molecular signalling through RAS/ERK, PI3K/AKT or JAK/STAT pathways. Aberrant activation of these pathways promotes survival, proliferation and motility of cancer cells, favouring HNSCC tumourigenesis

Figure 3

Mechanism of action of the human papillomavirus (HPV) on cell cycle regulation. To progress from G1 to S cell cycle phase, cells have to pass the G1 restriction point that is under the control of the retinoblastoma protein (pRb). pRb binds and represses E2F transcriptional factors. Mitogenic signalling through CyclinD1/CDK4 or CyclinD1/CDK6 phosphorylates pRb, promoting E2F release. CyclinE/CDK2 completes pRb phosphorylation, allowing S-phase entry. HPV affects the cell cycle by using two viral oncoproteins, E6 and E7. The E6 protein binds p53 and promotes its degradation, whereas E7 protein binds and inactivates pRb. These viral oncoproteins determine cell cycle entry and inhibition of p53-mediated apoptosis. HPV-dependent inhibition of pRb promotes p16 accumulation. p16 represents a surrogate marker of HPV-positive HNSCC