The expanding role of IAP antagonists for the treatment of head and neck cancer

Abstract

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.

Targeting Inhibitor of Apoptosis Proteins to Overcome Chemotherapy Resistance—A Marriage between Targeted Therapy and Cytotoxic Chemotherapy

“…Pre-clinical studies have shown that the IAP inhibitors are radio-and chemo-sensitizing in isolated cells, lab-grown organoids, and human tumors implanted in live mice. Concretely, IAP expression (in particular XIAP) seems to modulate the tumor microenvironment, and conversely, the tumor microenvironment seems to regulate IAP expression in tumor cells [22,34,41,42]. This evidence stemmed from ongoing early-phase clinical trials in which IAP inhibitors are combined with immunotherapy for solid tumors, namely the ASTEROID trial with tolinapant + pembrolizumab (NCT05082259) and a trial combining xevinapant with avelumab (NCT03270176).…”

“…In this paper, we review the theoretic underpinnings behind the effectiveness of xevinapant, as well as other apoptosis inducers such as birinapant and tolinapant, focusing on xevinapant, which has already shown clinical benefit in early-phase studies [22]. Then, we briefly review the pre-clinical data that supports the use of cIAP1/2 and XIAP inhibitors in clinical trials.…”

Taxanes in the Treatment of Head and Neck Squamous Cell Carcinoma

“…Survivin inhibits active caspase-9, thereby preventing apoptosis induced by aberrant mitosis resulting from mitotic damage caused by paclitaxel [89]. Other inhibitors of apoptosis proteins (IAP), including XIAP (X-linked inhibitor of apoptosis), cIAP1/2 (cellular inhibitor of apoptosis 1 and 2), and SMAC (second mitochondria-derived activator of caspases), have also been found to play crucial roles as survival factors in HNSCC [90]. Currently, clinical trials are underway to investigate the use of IAP antagonists for targeting HNSCC.…”