Radioresistance in head and neck squamous cell carcinoma: Biological bases and therapeutic implications

Head and neck squamous cell carcinoma (HNSCC) is
strongly associated with alcohol and tobacco consumption. Lately, the
incidence of human papillomavirus (HPV)-related tumors has shown a
significant increase, and HPV-related tumors show distinctive features if
compared with the HPV-negative counterpart. Locally advanced HNSCC
can be treated with concomitant chemoradiotherapy, but early recurrences
sometimes occur. Relapses are often related to an intrinsic radioresistance
of the tumors. Alterations in intracellular pathways, primarily
involved in cell proliferation, apoptosis, and DNA repair, can lead to
radioresistance. Preclinical and clinical evidence highlighted that 3 main
pathways, including the epidermal growth factor receptor (EGFR), the
phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin
(mTOR), and the p53 signaling cascades, play a crucial role in radioresistance
development. A future approach may consist in the association
of radiotherapy (RT) and selective inhibition of the key pathways involved
in radioresistance. Phase I, II, and III clinical trials are currently testing
these novel treatment strategies.