Many patients suffering from head and neck squamous cell carcinoma (HNSCC) do not benefit from cetuximab added to radiotherapy. Some of the mechansisms leading to resistance to the combined treatment are already understood. However, they do not fully explain the resistance to multimodal therapy. In this review, potential mechanisms of resistance to therapy will be addressed, starting from the outside of the cells looking at the potential role the ECM may play, then continuing with EGF receptor alterations, which may contribute to resistance to therapy with antibodies. The role of FcγRIIIa receptor polymorphism in antibody-dependent cell-mediated cytotoxicity (ADCC), which may be a mechanism of anticancer activity of cetuximab will be discussed, as well as the resistance to radiotherapy and receptor blocking therapy mediated by the insulin-like growth factor receptor I (IGF-1R). Inside the cell, proteins expressed in radioresistant cells will be highlighted before turning the attention to the impact epithelial mesenchymal transition (EMT) may have on increased resistance to different treatment modalities. The last section of this review aims to outline potential treatment approaches, which, in the future, may help improve treatment response.
Keywords: Resistance to radiotherapy, targeted therapy, combined therapy, squamous cell carcinoma of the head and neck (HNSCC), metalloproteinases, Polymorphisms, cytoskeleton, heterodimers, cetuximab