Overcoming the Impact of Hypoxia in Driving Radiotherapy Resistance in Head and Neck Squamous Cell Carcinoma

SIMPLE SUMMARY: Hypoxia (reduced oxygen availability) is common in the majority of tumours, including head and neck cancer, and it occurs due to an imbalance between oxygen supply and demand. One of the key problems with hypoxia in tumours is that these areas are more resistant to radiotherapy treatment, which in turn leads to a poor prognosis of patients. It is important that new therapeutic techniques in combination with radiotherapy are developed to overcome hypoxia within the tumour to increase patient survival. This review aims to consolidate our current understanding of how hypoxia leads to radioresistance in head and neck cancer, and discuss past and future strategies to overcome this. ABSTRACT: Hypoxia is very common in most solid tumours and is a driving force for malignant progression as well as radiotherapy and chemotherapy resistance. Incidences of head and neck squamous cell carcinoma (HNSCC) have increased in the last decade and radiotherapy is a major therapeutic technique utilised in the treatment of the tumours. However, effectiveness of radiotherapy is hindered by resistance mechanisms and most notably by hypoxia, leading to poor patient prognosis of HNSCC patients. The phenomenon of hypoxia-induced radioresistance was identified nearly half a century ago, yet despite this, little progress has been made in overcoming the physical lack of oxygen. Therefore, a more detailed understanding of the molecular mechanisms of hypoxia and the underpinning radiobiological response of tumours to this phenotype is much needed. In this review, we will provide an up-to-date overview of how hypoxia alters molecular and cellular processes contributing to radioresistance, particularly in the context of HNSCC, and what strategies have and could be explored to overcome hypoxia-induced radioresistance.