Abstract
Head and neck squamous cell carcinomas (HNSCCs) are a group of aggressive and genetically complex cancers, derived from the mucosal epithelium in the oral cavity, pharynx, and larynx. Radiotherapy, often combined with chemotherapy remains the mainstay treatment options for patients. But resistance to radiotherapy causes a critical hurdle in the treatment of HNSCC. Radiotherapy works by inducing the formation of DNA lesions, thus, resistance to irradiation involves the activation of the DNA damage response (DDR) pathways. Defects in DDR function accounts for eventual relapse and cancer progression. The receptor tyrosine kinase MET, and its sole ligand hepatocyte growth factor (HGF) are involved in a range of physiological and pathological processes in HNSCC. There is also compelling evidence suggesting that c-MET activation is crucial in conferring resistance to DNA-damaging agents such as irradiation in several tumour types via interaction with the DDR. Activation of the HGF/MET pathway has also been implicated in resistance to the only available targeted therapy in HNSCC, Cetuximab. Therefore, the HGF/MET axis represents a potentially valuable target for overcoming therapy resistance in HNSCC. Despite such strong evidence, the link between HGF/MET, DDR, and RT resistance in HNSCC has not been studied. This review aims to explore the crosstalk between c-MET and the DDR pathways in several tumour types and extend these findings specifically to HNSCC for exploiting HGF/MET in increasing radiosensitivity in HNSCC.