Inhibitors of apoptosis proteins (IAPs) inhibit the intrinsic and extrinsic cell death pathways, promoting cell survival. Antagonists of these pathways are under study as anti-cancer therapeutics. A high proportion of head and neck squamous cell carcinomas (HNSCCs) have genomic alterations in IAP pathways, resulting in the dysregulation of cell death pathways and rendering them susceptible to IAP antagonist therapy. Preclinical studies suggest IAP antagonists, also known as second mitochondria-derived activator of caspases mimetics, may be effective treatments for HNSCC, especially when combined with radiation. Mechanistic studies have shown both molecular mechanisms (i.e., enhanced cell death) and immune mechanisms (e.g., immunogenic cell death and T-cell activation), underlying the efficacy of these drugs in preclinical models. Phase I/II clinical trials have shown promising results, portending a future where this class of targeted therapies becomes incorporated into the treatment paradigm for head and neck cancers. IAP antagonists have shown great promise for head and neck cancer, especially in combination with radiation therapy. Here, we review recent preclinical and clinical studies on the use of these novel targeted agents for head and neck cancer.
Keywords: IAP antagonist; SMAC mimetic; birinapant; head and neck cancer; squamous cell carcinoma; tolinapant; xevinapant.
© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.