HGF/MET Signalling and DNA Damage Response: Strategies to Conquer Radiotherapy Resistance in Head and Neck Cancer

Head and neck squamous cell carcinomas (HNSCCs) are a heterogeneous group of aggressive malignancies strongly linked with chronic tobacco exposure, excessive alcohol consumption, and infection with high-risk subtypes of Human Papilloma Virus (HPV). Molecularly, HNSCC is classified into HPV-positive and HPV-negative sub-types [1]. Approximately 600,000 new cases are diagnosed annually with 380,000 deaths worldwide [2]. Despite our increased understanding of the viral and genetic mechanisms underlying HNSCC, the 5-year overall survival rate remains around 50% [3]. Radiotherapy (RT), chemotherapy (CT), surgical eradication, or a combination of all modalities are the current therapeutic options but are highly toxic and cause psychological distress and severely compromised quality of life, and hence associated with both symptomology and treatment survivors of this cancer have the second-highest mortality rate of suicide (63.4 per 100,000; [2000-2014]) [4]. The functional and aesthetic features of the head and neck anatomy are factors that make HNSCCs difficult to treat as tumours are located nearby critical anatomical structures which are sensitive to treatment. Radiotherapy (RT), chemotherapy (CT), surgical eradication, or a combination of all modalities are the current therapeutic options. Cetuximab is a monoclonal antibody (mAb) against the epidermal growth factor receptor (EGFR) and has been the only targeted FDA approved targeted therapy for HNSCC until the recent FDA approval of immunotherapy, but, both Cetuximab and immunotherapy clinical efficacy for HNSCC has been limited [5].