Evasion of apoptosis and treatment resistance in squamous cell carcinoma of the head and neck

Combinations of surgery, radiotherapy and chemotherapy can eradicate tumors in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN), but a significant proportion of tumors progress, recur, or do not respond to therapy due to treatment resistance. The prognosis for these patients is poor, thus new approaches are needed to improve outcomes. Key resistance mechanisms to chemoradiotherapy (CRT) in patients with LA SCCHN are alterations to the pathways that mediate apoptosis, a form of programmed cell death. Targeting dysregulation of apoptotic pathways represents a rational therapeutic strategy in many types of cancer, with a number of proteins, including the pro-survival B-cell lymphoma 2 family and inhibitors of apoptosis proteins (IAPs), having been identified as druggable targets. This review discusses the mechanisms by which apoptosis occurs under physiological conditions, and how this process is abnormally restrained in LA SCCHN tumor cells, with treatment strategies aimed at re-enabling apoptosis in LA SCCHN also considered. In particular, the development of, and future opportunities for, IAP inhibitors in LA SCCHN are discussed, in light of recent encouraging proof-of-concept clinical trial data.