Therapeutic Small Molecules Target Inhibitor of Apoptosis Proteins in Cancers with Deregulation of Extrinsic and Intrinsic Cell Death Pathways

The Cancer Genome Atlas (TCGA) has unveiled genomic deregulation of various components of the extrinsic and intrinsic apoptotic pathways in different types of cancers. Such alterations are particularly common in head and neck squamous cell carcinomas (HNSCC), which frequently display amplification and overexpression of the Fas-associated via death domain (FADD) and inhibitor of apoptosis proteins (IAP) that complex with members of the TNF receptor family. Second mitochondria-derived activator of caspases (SMAC) mimetics, modeled after the endogenous IAP antagonist SMAC, and IAP inhibitors represent important classes of novel small molecules currently in phase I/II clinical trials. Here we review the physiologic roles of IAPs, FADD, and other components involved in cell death, cell survival, and NF-κB signaling pathways in cancers, including HNSCC. We summarize the results of targeting IAPs in preclinical models of HNSCC using SMAC mimetics. Synergistic activity of SMAC mimetics together with death agonists TNFα or TRAIL occurred