REVIEW IAP-targeted therapies for cancer EC LaCasse 1,2,3 , DJ Mahoney 1,2,3 , HH Cheung 1,2,3 , S Plenchette 1,2 ,SBaird 1,2 and RG Korneluk 1,2 1 Apoptosis Research Centre, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada and 2 Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada DNA damage, chromosomal abnormalities, oncogene activation, viral infection, substrate detachment and hypoxia can all trigger apoptosis in normal cells. However, cancer cells acquire mutations that allow them to survive these threats that are part and parcel of the transformation process or that may affect the growth and dissemination of the tumor. Eventually, cancer cells accumulate further mutations that make them resistant to apoptosis mediated by standard cytotoxic chemo- therapy or radiotherapy. The inhibitor of apoptosis (IAP) family members, defined by the presence of a baculovirus IAP repeat (BIR) protein domain, are key regulators of cytokinesis, apoptosis and signal transduc- tion. Specific IAPs regulate either cell division, caspase activity or survival pathways mediated through binding to their BIR domains, and/or through their ubiquitin-ligase RING domain activity. These protein–protein interactions and post-translational modifications are the subject of intense investigations that shed light on how these proteins contribute to oncogenesis and resistance to therapy. In the past several years, we have seen multiple approaches of IAP antagonism enter the clinic, and the rewards of such strategies are about to reap benefit. Significantly, small molecule pan-IAP antagonists that mimic an endogenous inhibitor of the IAPs, called Smac, have demonstrated an unexpected ability to sensitize cancer cells to tumor necrosis factor-a and to promote autocrine or paracrine production of this cytokine by the tumor cell and possibly, other cells too. This review will focus on these and other developmental therapeutics that target the IAPs in cancer. Oncogene (2008) 27, 6252–6275; doi:10.1038/onc.2008.302 Keywords: XIAP; cIAP1; cIAP2; survivin; livin; birc Introduction The inhibitor of apoptosis (IAP) gene family regulates the cell’s decision to live or die in response to daily stresses and insults. In this review, we provide an overview of the mammalian IAPs, with particular emphasis on their many cellular roles in apoptosis suppression, signal transduction and proliferation. In addition, we address the relationship of the IAPs with cancer, and the various therapeutic modalities targeting these gene products for clinical benefit. The first discovered cellular, non-viral, IAP is the mammalian gene NAIP (Roy et al., 1995). The human IAPfamilyhasrapidlyexpandedtoincludesevenother members: XIAP, cIAP1, cIAP2 (Rothe et al., 1995; Duckett et al., 1996; Liston et al., 1996; Uren et al., 1996), ILP2 (Lagace et al., 2001; Richter et al., 2001), BRUCE(Hauser et al.,1998;Chen et al.,1999),survivin (Ambrosini et al., 1997) and livin (Vucic et al., 2000; Kasof and Gomes, 2001) (Figure 1 and Table 1). The IAPs, deserving of their name, effectively suppress apoptosis induced by a variety of stimuli, including death receptor activation, growth factor withdrawal, ionizing radiation, viral infection, endoplasmic reticu- lum stress and genotoxic damage (LaCasse et al., 1998; Liston et al., 2003; Cheung et al., 2006b; Hunter et al., 2007). The defining characteristic of the IAPs is a baculo- virus IAP repeat (BIR) domain. IAPs contain 1–3 BIR domains of 70–80 amino acids encoding a C2HC-type zinc-finger motif that tetrahedrally chelates one zinc atom, and forms a globular structure consisting of four or five a-helices and a variable number of antiparallel b-pleated sheets (Hinds et al., 1999; Sun et al., 1999). The two human IAPs, survivin and BRUCE, both with a role in cell mitosis (Ruchaud et al., 2007; Pohl and Jentsch, 2008), have an earlier evolutionary origin compared with the type 1 human members with roles in apoptosis and immunity (Robertson et al., 2006). In addition to BIR domains, IAPs contain various otherdomainsthataresummarizedinFigure1.Several mammalian IAP family members contain a carboxy- terminal RING (really interesting new gene) zinc-finger domain. In XIAP, cIAP1 and cIAP2, this RING domain has been shown to possess E3 ubiquitin ligase activity,directlyregulatingauto-ortrans-ubiquitination andproteindegradation(Yang et al.,2000;Suzuki et al., 2001; Silke et al., 2005; Cheung et al., 2008). Within the IAP family, the presence of a CARD domain is unique to cIAP1 and cIAP2 (Figure 1). The Correspondence: Dr EC LaCasse, Apoptosis Research Centre, Children’sHospitalofEasternOntario,CHEORI2,401SmythRoad, Ottawa, Ontario, Canada K1H 8L1. E-mail: eric@arc.cheo.ca 3 These three authors contributed equally to this work. Oncogene (2008) 27, 6252–6275 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc