Mechanisms of resistance in head and neck cancer

Resistance to treatment is one of the biggest challenges in combating head and neck squamous cell carcinoma (HNSCC). The concept of resistance, however, is often viewed as a whole without categorization into the two types of resistance: acquired and intrinsic. Comparison of the mechanisms of the two types of resistance can give further insight as to the importance of these resistance pathways, as mechanisms that are common between the two categories are more likely to be integral to cell survival. In this review, a new perspective on resistance is presented in order to identify molecular targets that have potential for wide therapeutic application. Resistance mechanisms are grouped by the primary pathway involved in order to help establish connections between studies and identify the pathways most active in HNSCC resistance. The receptor tyrosine kinase AXL is one of the targets that showed the greatest promise for overcoming resistance to cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), as it is shown to be upregulated in both acquired and intrinsically cetuximab-resistant cells. Other targets of interest are signal transducer and activator of transcription 3 (STAT3), a downstream transcription factor of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, and TWIST, a marker of epithelial-mesenchymal transition. STAT3 has been shown to be upregulated and more active in cetuximab-resistant HNSCC cell lines, and its inhibition decreased cell growth in cell lines resistant to anti-EGFR therapy. Twist has been shown to have roles in acquired resistance for both cetuximab and cisplatin, a platinum-based therapy that targets dividing cells, which suggests that it also has an integral role in resistance. Other resistance mechanisms are also summarized in this review, but further studies are needed in order to confirm their utility as targets for overcoming resistance in HNSCC.