Targeted therapies for non-HPV-related head and neck cancer: challenges and opportunities in the context of predictive, preventive, and personalized medicine.

Head and neck squamous cell carcinoma (HNSCC) develops in the mucosal lining of the upper aerodigestive tract, principally as a result of exposure to carcinogens present in tobacco products and alcohol, with oncogenic papillomaviruses also being recognized as etiological agents in a limited proportion of cases. As such, there is considerable scope for prevention of disease development and progression. However, despite multimodal approaches to treatment, tumor recurrence and metastatic disease are common problems, and clinical outcome is unsatisfactory. As our understanding of the genetics and biochemical aberrations in HNSCC has improved, so the development and use of molecularly targeted drugs to combat the disease have come to the fore. In this article, we review molecular mechanisms that alter signal transduction downstream of the epidermal growth factor receptor (EGFR) as well as those that perturb orderly cell cycle progression, such as p53 mutation, cyclin overexpression, and loss of cyclin-dependent kinase inhibitor function. We outline some of the tactics that have been employed to combat the altered biochemistry. These include blockade of the EGFR using humanized monoclonal antibodies such as cetuximab and small molecule tyrosine kinase inhibitors (TKIs) such as erlotinib/gefitinib and subsequent generations of TKIs, restoration of p53 function using MIRA compounds, and inhibition of cyclin-dependent kinase and aurora kinase activity using drugs such as palbociclib and alisertib. Knowledge of the underlying molecular mechanisms may be utilizable in order to predict disease behavior and tailor therapeutic interventions in a more personalized approach to improve clinical response. Use of liquid biopsy, omics platforms, and salivary diagnostics hold promise in this regard.