title: Therapeutic Small Molecules Target Inhibitor of Apoptosis Proteins in Cancers with Deregulation of Extrinsic and Intrinsic Cell Death Pathways.
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 (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 occurredin vitro, whereas their antitumor effects were augmented when combined with radiation and chemotherapeutic agents that induce TNFαin vivoIn 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.Clin Cancer Res; 23(6); 1379-87. ©2016 AACR.
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland.
authors.forename: Adeeb
authors.initials: A
authors.lastname: Derakhshan
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland. vanwaesc@nidcd.nih.gov chenz@nidcd.nih.gov.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland. vanwaesc@nidcd.nih.gov chenz@nidcd.nih.gov.
authors.forename: Carter
authors.initials: C
authors.lastname: Van Waes
mesh_terms: D065091:Amylin Receptor Agonists / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D053200:Fas-Associated Death Domain Protein / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D065091:Amylin Receptor Agonists; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha