Therapeutic small-molecules target inhibitor of apoptosis proteins in cancers with deregulation of extrinsic and intrinsic cell death pathways.

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Therapeutic small-molecules target inhibitor of apoptosis proteins in cancers with deregulation of extrinsic and intrinsic cell death pathways.

Clin Cancer Res. 2016 Dec 30;:

Authors: Derakhshan A, Chen Z, Van Waes C

Abstract
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 (IAPs), that complex with members of the tumor necrosis factor (TNF) receptor family. SMAC mimetics, modeled after the endogenous IAP antagonist second mitochondria-derived activator of caspases (SMAC), and IAP inhibitors, represent important classes of novel small-molecules currently in phase I/II clinical trials. Here we review the physiological roles of IAPs, FADD, and other components involved in cell death, 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 in vitro, while their anti-tumor effects were augmented when combined with radiation and chemotherapeutic agents that induce TNFα in vivo. In addition, clinical trials testing SMAC mimetics as single agents or together with chemo- or radiation therapies in patients with HNSCC and solid tumors are summarized. As we achieve a deeper understanding of the genomic alterations and molecular mechanisms underlying deregulated death and survival pathways in different cancers, the role of SMAC mimetics and IAP inhibitors in cancer treatment will be elucidated. Such developments could enhance precision therapeutics and improve outcomes for cancer patients.

PMID: 28039268 [PubMed - as supplied by publisher]

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