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Antagonists of IAP proteins as cancer therapeutics
Cancer Letters 332 (2013) 206–214
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Cancer Letters journal homepage: www.elsevier.com/locate/canlet
Mini-review
Antagonists of IAP proteins as cancer therapeutics Jasmin N. Dynek, Domagoj Vucic ⇑ Department of Protein Engineering, Genentech, Inc., South San Francisco, CA 94080, USA
a r t i c l e
i n f o
Keywords: IAP Antagonist Apoptosis XIAP c-IAP SMAC TNF
a b s t r a c t Inhibitor of apoptosis (IAP) proteins play pivotal roles in cellular survival by blocking apoptosis, modulating signal transduction, and affecting cellular proliferation. Through their interactions with inducers and effectors of apoptosis IAP proteins can effectively suppress apoptosis triggered by diverse stimuli including death receptor signaling, irradiation, chemotherapeutic agents, or growth factor withdrawal. Evasion of apoptosis, in part due to the action of IAP proteins, enhances resistance of cancer cells to treatment with chemotherapeutic agents and contributes to tumor progression. Additionally, IAP genes are known to be subject to amplification, mutation, and chromosomal translocation in human malignancies and autoimmune diseases. In this review we will discuss the role of IAP proteins in cancer and the development of antagonists targeting IAP proteins for cancer treatment. Ó 2010 Elsevier Ireland Ltd. All rights reserved.
1. The IAP family: structure Originally discovered in baculoviruses [1–3], the IAP gene family is highly conserved throughout evolution with homologues in both invertebrates and vertebrates. The human family of IAP proteins consists of 8 members: cellular IAP 1 (c-IAP1)/HAIP2/MIHB/BIRC2, cellular IAP 2 (c-IAP2)/ HIAP1/MIHC/BIRC3, X-chromosome linked IAP (XIAP)/ hILP/MIHA/BIRC4, neuronal apoptosis inhibitory protein (NAIP)/BIRC1, melanoma IAP (ML-IAP)/KIAP/livin/BIRC7, survivin/TIAP/BIRC5, Apollon/BRUCE/BIRC6, and IAP like protein 2 (ILP2)/Ts-IAP/BIRC8 [4,5]. All IAP proteins characteristically contain at least one baculovirus IAP repeat (BIR) domain, a 70–80 amino acid zinc-binding domain consisting of a conserved a/b fold [6,7] (Fig. 1). Beyond the BIR domain, the majority of human IAP proteins also harbor a carboxy terminal RING (really interesting new gene) domain. The RING domains of c-IAP1, c-IAP2, ML-IAP and XIAP have demonstrated E3 ubiquitin ligase activity, and as such are capable of performing auto-ubiquitination as well as trans-ubiquitination of their ⇑ Corresponding author. Address: Department of Protein Engineering, Genentech, Inc., 1 DNA Way, M/S 40, South San Francisco, CA 94080, USA. Tel.: +1 650 225 8839; fax: +1 650 225 6127. E-mail address: [email protected] (D. Vucic). 0304-3835/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.canlet.2010.06.013
binding partners [8]. Apollon lacks a RING domain, but it does contain an ubiquitin conjugating domain (UBC) that is also capable of promoting ubiquitination [9,10]. Another common feature shared by c-IAP1, c-IAP2, XIAP and ILP2 is an evolutionarily conserved ubiquitin-associated (UBA) domain that mediates binding of c-IAP1, c-IAP2 and XIAP to ubiquitin moieties [11,12]. The presence of a caspase recruitment domain (CARD) in c-IAP1 and c-IAP2 is anticipated to mediate protein–protein interactions although a binding partner has not yet been identified [13,14]. Survivin possesses a coiled-coil (CC) domain responsible for its interaction with chromosomal passenger proteins (CPC) during cell division [15]. NAIP contains a nucleotide-binding and oligomerization domain (NOD) and a leucine-rich repeat (LRR) domain, which along with its cellular function in innate immunity has lead to the classification of NAIP as a member of the NOD-like receptor family (Fig. 1) [16,17].
2. IAP function: caspase inhibition and modulation of cell survival signaling pathways IAP proteins inhibit apoptosis provoked by stimuli that signal through either intrinsic, such as intracellular damage, or extrinsic, in the case of signaling via death receptor complexes, pathways (Fig. 2) [5,18]. Both of these
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NAIP c-IAP1 c-IAP2 XIAP ML-IAP ILP-2 survivin Apollon BIR
RING
Coiled coil
CARD
UBA
UBC
NACHT LRR
Fig. 1. The human IAP protein family. Human IAP proteins contain one or three baculovirus IAP repeat (BIR) domains. Several IAP family members possess RING (really interesting new gene) and UBA (ubiquitin-associated) domains. The c-IAP1 and c-IAP2 proteins also each contain a caspase recruitment domain (CARD). Survivin contains a coiled-coil domain; NAIP has NACHT (domain present in NAIP, CIITA, HET-E, TP1) and leucine-rich repeat (LRR) domains; Apollon possesses a ubiquitin conjugating (UBC) domain.
pathways converge at the level of activation of caspases, cysteine-dependent aspartyl-specific proteases that are critical for the execution of programmed cell death [19]. XIAP can directly bind to and potently inhibit caspase-3, caspase-7, and caspase-9 [20]. Inhibition of different classes of caspases by XIAP is mediated by an elegant binding scheme. Structural studies have revealed that XIAP inhibits caspases-3 and -7 by preventing substrate entry and catalysis via binding of an XIAP linker region, located just upstream of its BIR2 domain, to the caspase active sites [7]. Additionally, a surface peptide-binding groove of the BIR2 domain of XIAP binds to the processed amino-terminus of the small subunit of caspase-3, which is exposed upon proteolytic processing of caspase-3 [21]. Inhibition of caspase-9 is accomplished through two separate interactions within the XIAP BIR3 domain; the peptide-binding groove of BIR3 interacts with the amino-terminus of the small subunit of caspase-9, while another region of BIR3 binds to the caspase-9 homodimerization interface, thereby preventing caspase-9 dimerization and activation [22,23]. Potent inhibition of caspases by XIAP can be counteracted by the mitochondrial protein SMAC (second mitochondria-derived activator of caspases)/DIABLO (direct IAP-binding protein with low pI) [24,25]. Upon apoptotic signaling SMAC is released from mitochondria into the cytosol where it can bind XIAP and abrogate its caspaseinhibitory activity [24–26] (Fig. 2). SMAC contains a fourresidue long highly conserved IAP-binding motif (IBM; AV-P-I), that is exposed at the amino-terminus of the mature processed protein and competes with caspases for binding to the same surface peptide-binding grooves in the BIR domains of IAP proteins [5]. No other human IAP proteins examined, besides XIAP, have been proven to be potent physiological inhibitors of caspases [27–29]. However c-
IAP1, c-IAP2 and ML-IAP are each capable of binding to SMAC and effectively sequestering it away from XIAP, allowing XIAP to inhibit caspases and ultimately block apoptosis [28,30]. Additionally, c-IAP1, c-IAP2, XIAP, MLIAP, and Apollon are able to target caspases and SMAC for proteasomal degradation via their activity as E3 ubiquitin ligases [8,31,32]. Cellular IAP proteins exert a major impact on survival signaling pathways by way of their E3 ligase activity. Tumor necrosis receptor-associated factor 2 (TRAF2), an adaptor protein that functions in both canonical and noncanonical nuclear factor B (NF-jB) signaling pathways, interacts with c-IAP1 and c-IAP2 and recruits them to tumor necrosis factor (TNF) receptor complexes [5,18]. In the NF-jB canonical pathway c-IAP1 and c-IAP2 promote activation of signaling by their ubiquitination of receptor interacting protein (RIP1) (Fig. 3) [33–36]. However, in noncanonical NF-jB signaling, c-IAP proteins have been identified as the E3 ligases responsible for the ubiquitination and subsequent degradation of NF-jB-inducing kinase (NIK), and thus serve as negative regulators of this signaling pathway [37,38] (Fig. 3). Also, c-IAP1 has been shown to potentiate the activity of the oncogene Myc by promoting ubiquitination and proteasomal degradation of the Myc inhibitory protein, Mad1 [39]. The smallest, single BIR-containing, IAP protein survivin is primarily involved in cell division, not apoptosis. Transcription of survivin is upregulated during the G2M phase of the cell cycle and survivin controls cell division via its interactions with proteins of the chromosomal passenger complex (CPC) [40,41]. Likewise, recent studies suggest that Apollon functions mainly in cell division, and may potentially cooperate with survivin during cytokinesis [42]. NAIP, the first-discovered human member of the IAP protein family, is capable of preventing apoptosis provoked
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Apo2L/FasL
Extrinsic TNF•
Intrinsic
DR/Fas TNF-R1
FADD
TRADD TRAF2
Mitochondria
Caspase-8
tBid Bid
c-IAP 1/2
RIP1 FLIP
ML-IAP
FLIP
Bcl-2 Bcl-XL Cytochrome C
Active Caspase-8
SMAC
Caspase-8
TRADD c-IAP 1/2
XIAP
RIP1 TRAF2
Caspase-9 Active Caspase-9 Apoptosome
Caspase-3/7 Active Caspase-3/7
Apoptosis
Fig. 2. The intrinsic and extrinsic apoptotic pathways. Programmed cell death is initiated in the intrinsic pathway by irradiation, growth factor withdrawal, or chemotherapeutic agents. Following neutralization of the anti-apoptotic proteins Bcl-2, Bcl-xL, and Mcl-1 and disruption of the mitochondrial membrane potential, cytochrome c and SMAC are released from the mitochondria into the cytoplasm. This leads to activation of caspase-9, subsequent activation of caspases-3 and -7, and ultimately cell death. Apoptotic signaling through the extrinsic pathway is triggered by binding of death ligands, such as TNFa and FasL, to their cognate death receptors, in this case TNF-R1 and Fas, respectively, which results in recruitment of the adaptor protein FADD and caspase-8. This leads to the activation of caspase-8, then caspases-3 and -7, and finally apoptosis. XIAP can inhibit caspases-3, -7, and -9; however, SMAC can bind to XIAP and prevent XIAP-mediated inhibition of caspases. ML-IAP, c-IAP1, and c-IAP2 can sequester SMAC away from XIAP, thus preventing its pro-apoptotic activity.
by a variety of apoptotic stimuli [16,43]. However, NAIP is generally not considered to be a true inhibitor of apoptosis. Rather, NAIP’s predominant role is probably in innate immunity where it mediates the host defense against intracellular pathogens [44,45]. ILP2, a tissue-specific homologue of XIAP, is inherently unstable and has not yet been demonstrated to inhibit apoptosis under physiological conditions [46].
3. Negative regulators of IAP proteins A subset of IAP-binding partners operates as endogenous inhibitors of IAP proteins, contributing to the finetuned balance between anti- and pro-apoptotic signaling in cells. As discussed in the previous section, SMAC is an endogenous IAP antagonist that binds to the BIR domains of IAP proteins via a conserved IAP-binding motif. Similarly, human High temperature requirement protein A2 (HtrA2/Omi) is a protein whose mature processed form is released from the mitochondria upon apoptotic signaling,
binds to IAP BIR domains via its IBM, and blocks IAP-mediated inhibition of cell death [47,48]. Additionally, HtrA2/ Omi possesses serine protease activity that contributes to its pro-apoptotic role [47,48]. Of note, both the IBM sequence and the mechanism of IAP regulation is conserved in the Drosophila IAP antagonists Reaper, Hid, Grim, and Sickle [49]. Several other BIR domains-binding proteins were identified through genomic screens (i.e. Nipsap or Nsp4, leucine-rich pentatricopeptide repeat motif-containing protein or LRPPR, 3 hydroxyisobutyrate dehydrogenase or 3HB) [50]. However, their functional significance in regulation of IAP-mediated inhibition of cell death is not yet apparent. XIAP-associated factor 1 (XAF1) was discovered in a yeast-two-hybrid screen for XIAP-interacting proteins, and acts as an endogenous inhibitor of XIAP [51]. XAF1 is a nuclear protein that has been shown to sequester XIAP in the nucleus, thus preventing XIAP-mediated inhibition of caspases in the cytosol [51]. Also XAF1 has been reported to interact with c-IAP1/2, ML-IAP, ILP2 and NAIP but not survivin, although a XIAP–XAF1 complex can indi-
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CD40L, TWEAK
TNF•
TNF-R1
TRADD TRAF2
CD40R, FN-14
TRAF2
TRAF3
TRAF2 c-IAPs c-IAPs
RIP1 Ub Ub NEMO 63 Ub IKK• IKK• P
NIK 48 Ub
Ub Ub
Ub
P IKK•
IKK• Proteasome
UbUb 48 Ub P I•B
P p100 RelB
p50 RelA
P p52 RelB
Proteasome p50 RelA
p52 RelB Gene Expression
Nucleus
Fig. 3. Canonical and noncanonical NF-jB pathways. NF-jB signaling occurs via canonical and noncanonical pathways. Signaling through the TNF-R1 complex activates the canonical pathway, wherein binding of TNFa to TNF-R1 triggers recruitment of the adaptor protein TRADD, which in turn leads to the recruitment of TRAF2, RIP1, c-IAP1 and c-IAP2. RIP1 is then subject to c-IAP1/2-mediated ubiquitination by a variety of polyubiquitin linkages including K63 linkage. This modification facilitates assembly of the RIP1-associated kinase complexes, TAK1/TABs and IKK, leading to the phosphorylation and proteasomal degradation of IjB that enables NF-jB dimers to translocate to the nucleus and induce gene expression. Other receptors, such as FN14 or CD40R, can activate the noncanonical NF-jB signaling pathway. In this pathway c-IAP1/2 are recruited to receptor complexes by TRAF2, where they function as E3 ligases to promote K48-linked polyubiquitination and proteasomal degradation of NIK, and thus negatively regulate noncanonical NF-jB signaling.
rectly promote the proteasomal degradation of survivin [52]. Despite a lack of any recognizable IBM, XAF1 interacts with the BIR domains of IAP proteins; the exact mechanism of XAF1 IAP-antagonist activity and how the XIAP–XAF1 interaction is regulated is not known at present [53,54]. 4. IAP proteins in cancer Multiple lines of evidence have proven that IAP proteins are involved in cancer and other human malignancies. Firstly, a number of studies have demonstrated that elevated expression levels of IAP proteins, particularly cIAP1/2 and XIAP, in a number of tumor types correlates with a poor prognosis [5]. Survivin expression is undetectable in the majority of adult tissues, however, it is highly expressed in most human tumors [41]. Likewise, ML-IAP is not expressed in most normal human tissues but is frequently expressed at high levels in melanomas, bladder, and kidney cancers [55–59]. Additionally, expression of ML-IAP in melanomas is regulated by the lineage survival oncogene microphthalmia-associated transcription factor
(MITF), suggesting that the anti-apoptotic activity of MLIAP contributes to the pro-survival properties of MITF in melanoma progression [60]. Secondly, a number of animal and in vitro studies have further explored and illuminated the oncogenic potential of IAP proteins. In tumor cells down-regulation of XIAP expression, either by RNA interference or antisense oligonucleotides, results in stimulation of apoptosis and sensitization to gamma-irradiationand chemotherapeutic-induced apoptosis, both in vitro and in vivo [61–64]. Likewise, down-regulation of c-IAP1, ML-IAP, or survivin leads to activation of apoptotic pathways and increased sensitivity to cell death stimuli, such as chemotherapeutic agents and death receptors [5,41]. Lastly, direct genetic data established that c-IAP1/2 are potential pro-oncogenes. The chromosomal region 11q21– q23 containing c-IAP1 and c-IAP2 is subject to chromosomal amplification in esophageal squamous cell carcinomas, renal cell carcinomas, glioblastomas, gastric carcinomas, non-small cell lung carcinomas and other tumor types [5,18]. In murine tumors the syntenic region encompassing the c-IAP1 and c-IAP2 genes is also
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amplified, and ectopic overexpression of c-IAP1 in mouse models has been demonstrated to lead to tumor growth and hepatoma formation [65]. More genetic evidence comes from studies of an extranodal non-Hodgkin lymphoma, termed MALT lymphoma, where in around 50% of the cases surveyed the t(11,18)(q21;q21) translocation leads to a fusion of the BIR domains of c-IAP2 with the carboxy terminus of the paracaspase/MALT1 (mucosa-associated lymphoid tissue protein) [66–69]. The resultant c-IAP2:MALT1 fusion protein promotes constitutive activation of the NF-jB pathway, leading to increased pro-survival and inflammatory pathway signaling, as well as greater resistance to chemotherapeutic anti-tumor agents [70–72].
5. IAP proteins as targets in cancer therapy The significant problem of acquired chemotherapeutic resistance in tumor cells is a major concern in cancer therapy and targeting IAP proteins presents a potential therapeutic avenue to combat this challenge. A number of strategies to target IAP proteins in cancer are being explored. Herein the focus will center on the generation of reagents that mimic the amino-terminus of mature SMAC, the endogenous IAP antagonist. SMAC mimetics, including both SMAC derived peptides and small molecule antagonists, disrupt IAP:caspase and IAP:SMAC interactions, and stimulate cell death [5,73]. Additionally, work from Fulda et al., and other groups, demonstrated that SMAC-based peptides could significantly sensitize tumor cell lines to apoptosis induced by chemotherapeutics and death receptor agonists [74–77]. The first wave of small-molecule IAP antagonist were ‘monomeric’ compounds (Fig. 4) that bind to the BIR3 domains of XIAP, c-IAP1 and c-IAP2, and to the single BIR domain of ML-IAP [30,78–81]. Subsequently, ‘dimeric’ compounds (Fig. 4) were identified, initially by the serendipitous discovery of the bivalent Smac mimetic Compound 3, and later through an intentional structure-based design [78,82]. Several different binding assays indicated that bivalent compounds had higher affinity for full-length and BIR2–BIR3 containing IAP constructs compared to monovalent IAP antagonists, suggesting a two-site binding model [37,83,84]. In addition, analytical ultracentrifugation and gel filtration indicated that the bivalent antagonists induced dimerization of c-IAP1 BIR2–BIR3 and XIAP BIR3-only constructs, but not of an XIAP BIR2–BIR3 construct [37,83,84]. Bivalent IAP antagonists are extremely potent antagonists of IAPmediated anti-apoptotic activity [37,82,84]. This increased potency can be partly explained by their capacity to induce c-IAP dimerization, leading to more pronounced degradation of c-IAP1 and c-IAP2 [37]. But more importantly, the ability of bivalent IAP antagonists to engage BIR2 and BIR3 of XIAP at the same time results in a pronounced abrogation of XIAP-mediated caspase inhibition [85,86]. This strong caspase-3/7 activation is probably the major reason for the superior pro-apoptotic and anti-tumor activity of bivalent antagonists in comparison to monovalent compounds that can bind only one BIR domain at a time. Unexpectedly, studies from our group and others found that the ability of small-molecule IAP antagonists to induce
apoptosis relies largely on their induction of c-IAP1/2 autoubiquitination and proteasomal degradation, which in turn leads to the activation of NF-jB pathways and caspase-8dependent apoptosis in tumor cells [34,37,38,80,87,88]. IAP antagonist-induced activation of both the canonical and noncanonical NF-jB pathways leads to increased expression of the NF-jB responsive gene TNFa, which in the absence of c-IAP proteins promotes apoptosis by binding to TNF-R1, triggering TNFR-mediated signaling and activating caspase-8 [37,38,87] (Fig. 3). The application of TNF-blocking reagents or knockdown of TNF-R1 inhibited IAP antagonist-stimulated apoptosis, thus revealing that small-molecule IAP antagonist-induced cell death requires TNF signaling [37,38,80,87]. These studies provide strong evidence that targeting IAP proteins, namely cellular IAPs, with IAP antagonists results in heightened physiological TNF-receptor apoptotic signaling and apoptosis in tumor cells. By design IAP antagonists target a broad range of human IAP proteins. Nonetheless, there have been efforts towards developing IAP antagonists that selectively target either c-IAP1/2 or XIAP. A c-IAP-selective IAP antagonist has been engineered that possesses high selectivity for binding of c-IAP proteins over XIAP and can elicit c-IAP degradation, NF-jB pathway activation, and apoptosis in tumor cells (Fig. 4) [89]. However, in short- and long-term tumor cell survival assays the c-IAP-selective IAP antagonist was less effective at inducing cell death when compared with the pan-IAP antagonist, indicating that antagonism of both XIAP and c-IAP proteins is likely required for the most robust induction of apoptosis in cancer cells [89]. Two different strategies targeting XIAP:caspase3 interactions have been employed to selectively antagonize the anti-apoptotic activity of XIAP. One group discovered a small-molecule inhibitor of the XIAP:caspase-3 interaction by way of high-throughput biochemical screening, and showed that this XIAP specific antagonist could restore sensitivity to a particular apoptotic stimuli (Apo2L/ TRAIL) in a resistant tumor cell line [90]. Through a combinatorial chemistry library screen another group found a class of small molecules called polyphenylureas that can reverse XIAP-mediated inhibition of caspase-3, but not caspase-9, and promote anti-tumor activity in vitro and in vivo [91]. Collectively, these studies of c-IAP- and XIAP-selective antagonists have augmented our knowledge of the molecular mechanisms of IAP antagonism and further validated the applicability of targeting IAP proteins for cancer treatment. Small-molecule IAP antagonists and SMAC-based peptides have demonstrated efficacy in the treatment of breast cancer, non-small cell lung cancer, malignant glioma, and multiple myeloma models in vivo, suggesting that they may hold great promise for the treatment of cancer [5,78]. Currently, small-molecule IAP antagonists from Genentech, Inc., Novartis, Aegera Therapeutics/Human Genome Sciences, TetraLogic Pharmaceuticals, Ascenta Therapeutics, Joyant Pharmaceuticals, and possibly other institutions have entered, or are preparing to enter, clinical trials [78]. These Phase I trials will explore the safety and pharmacokinetcs of monovalent and bivalent IAP antagonists for the treatment of human malignancies. Preclinical
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H N
N H O
O
H N
N H
O O
N H
O N
O
N
O
H N
N H O
O
O H N
N H
MV1
BV6
O
N O
O
N H
H N
O
H N
O N H
H N
N O
O
NH
O N H
N N
CS3
N O
N
Cl
S
PS1
N
Fig. 4. Structural representation of examples of ‘monomeric’ (MV1), ‘dimeric’ (BV6), c-IAP selective (CS3) and pan-IAP antagonists (PS1).
data suggest that the bivalent compounds could be more efficacious but due to their size, these reagents will likely be administered intravenously with less frequent dosing. Monovalent antagonists, on the other hand, could potentially be administered orally and more frequently, which may enable more continuous IAP antagonism. Hopefully, ongoing and forthcoming clinical trials will answer these questions and pave the way for future clinical investigations of IAP-regulated apoptotic pathways. An early report from the Phase I study of LCL161, an orally bioavaliable IAP antagonist, indicates that this treatment was well tolerated in cancer patients with no doselimiting toxicities reported [92]. Treatment with LCL161 also demonstrated target antagonism as shown by degradation of c-IAP1 protein 2 h post-dose and subsequent upregulation of circulating cytokines such as MCP-1 and IL-8 [92]. However, since the degradation of c-IAP1 protein can be expected in non-tumor tissues, as well as in responsive and nonresponsive malignancies, it is likely that cIAP1 degradation could serve as an indicator of IAP-antagonist activity, but not as a predictive marker. Therefore, it will be exceedingly important to identify the predictive marker(s) that would allow selection of the patient population(s) that will benefit the most from this therapeutic approach. Thus far, it is clear that TNFa is critical for the single-agent activity of IAP antagonists in cancer cells, but it is far less obvious how instrumental local, or systemic, TNFa will be for the anti-tumor activity of IAP-targeting compounds. In addition to showing single-agent anti-tumor activity in in vivo mouse models, IAP antagonists also exhibit synergy in combination with a number of pro-apoptotic and anti-proliferative agents [86,93–99]. IAP antagonists enhanced apoptosis induced by pro-apoptotic receptor ago-
nists, such as TRAIL/Apo2L, FasL, and anti-DR5 antibody in various human cancer cell lines, and augmented TRAIL/Apo2L’s or anti-DR5’s anti-tumor activity in a mouse xenograft model [86,95,97,99]. Additionally, IAP antagonists were demonstrated to synergize with well-established cytotoxic chemotherapeutics in human prostrate cancer and non-small cell lung cancer (NSCLC) cells, as well as in mouse xenograft and transgenic models of pancreatic cancer [93,94,98]. Future clinical trials designed to test these combinations, and diagnostic efforts aimed at identifying treatment-suitable population(s), should provide novel therapeutic opportunities for cancer patients. In conclusion, due to their potent anti-apoptotic activity and elevated expression in many tumor types, the IAP proteins have proven to be promising targets for therapeutic intervention in cancer. Continued research efforts to elucidate the myriad aspects of IAP functions within apoptosis, signal transduction pathways, protein turnover, and cell division harbor the potential to lead to new therapeutic strategies.
Conflict of interest Both authors are employees of Genentech, Inc.
Acknowledgments The authors thank Kurt Deshayes, Wayne J. Fairbrother, Eugene Varfolomeev and Tatiana Goncharov for helpful discussion, critical reading of the manuscript and help with the figure design. Both authors are employees of Genentech, Inc.
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Contents lists available at SciVerse ScienceDirect
Cancer Letters journal homepage: www.elsevier.com/locate/canlet
Mini-review
Antagonists of IAP proteins as cancer therapeutics Jasmin N. Dynek, Domagoj Vucic ⇑ Department of Protein Engineering, Genentech, Inc., South San Francisco, CA 94080, USA
a r t i c l e
i n f o
Keywords: IAP Antagonist Apoptosis XIAP c-IAP SMAC TNF
a b s t r a c t Inhibitor of apoptosis (IAP) proteins play pivotal roles in cellular survival by blocking apoptosis, modulating signal transduction, and affecting cellular proliferation. Through their interactions with inducers and effectors of apoptosis IAP proteins can effectively suppress apoptosis triggered by diverse stimuli including death receptor signaling, irradiation, chemotherapeutic agents, or growth factor withdrawal. Evasion of apoptosis, in part due to the action of IAP proteins, enhances resistance of cancer cells to treatment with chemotherapeutic agents and contributes to tumor progression. Additionally, IAP genes are known to be subject to amplification, mutation, and chromosomal translocation in human malignancies and autoimmune diseases. In this review we will discuss the role of IAP proteins in cancer and the development of antagonists targeting IAP proteins for cancer treatment. Ó 2010 Elsevier Ireland Ltd. All rights reserved.
1. The IAP family: structure Originally discovered in baculoviruses [1–3], the IAP gene family is highly conserved throughout evolution with homologues in both invertebrates and vertebrates. The human family of IAP proteins consists of 8 members: cellular IAP 1 (c-IAP1)/HAIP2/MIHB/BIRC2, cellular IAP 2 (c-IAP2)/ HIAP1/MIHC/BIRC3, X-chromosome linked IAP (XIAP)/ hILP/MIHA/BIRC4, neuronal apoptosis inhibitory protein (NAIP)/BIRC1, melanoma IAP (ML-IAP)/KIAP/livin/BIRC7, survivin/TIAP/BIRC5, Apollon/BRUCE/BIRC6, and IAP like protein 2 (ILP2)/Ts-IAP/BIRC8 [4,5]. All IAP proteins characteristically contain at least one baculovirus IAP repeat (BIR) domain, a 70–80 amino acid zinc-binding domain consisting of a conserved a/b fold [6,7] (Fig. 1). Beyond the BIR domain, the majority of human IAP proteins also harbor a carboxy terminal RING (really interesting new gene) domain. The RING domains of c-IAP1, c-IAP2, ML-IAP and XIAP have demonstrated E3 ubiquitin ligase activity, and as such are capable of performing auto-ubiquitination as well as trans-ubiquitination of their ⇑ Corresponding author. Address: Department of Protein Engineering, Genentech, Inc., 1 DNA Way, M/S 40, South San Francisco, CA 94080, USA. Tel.: +1 650 225 8839; fax: +1 650 225 6127. E-mail address: [email protected] (D. Vucic). 0304-3835/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.canlet.2010.06.013
binding partners [8]. Apollon lacks a RING domain, but it does contain an ubiquitin conjugating domain (UBC) that is also capable of promoting ubiquitination [9,10]. Another common feature shared by c-IAP1, c-IAP2, XIAP and ILP2 is an evolutionarily conserved ubiquitin-associated (UBA) domain that mediates binding of c-IAP1, c-IAP2 and XIAP to ubiquitin moieties [11,12]. The presence of a caspase recruitment domain (CARD) in c-IAP1 and c-IAP2 is anticipated to mediate protein–protein interactions although a binding partner has not yet been identified [13,14]. Survivin possesses a coiled-coil (CC) domain responsible for its interaction with chromosomal passenger proteins (CPC) during cell division [15]. NAIP contains a nucleotide-binding and oligomerization domain (NOD) and a leucine-rich repeat (LRR) domain, which along with its cellular function in innate immunity has lead to the classification of NAIP as a member of the NOD-like receptor family (Fig. 1) [16,17].
2. IAP function: caspase inhibition and modulation of cell survival signaling pathways IAP proteins inhibit apoptosis provoked by stimuli that signal through either intrinsic, such as intracellular damage, or extrinsic, in the case of signaling via death receptor complexes, pathways (Fig. 2) [5,18]. Both of these
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NAIP c-IAP1 c-IAP2 XIAP ML-IAP ILP-2 survivin Apollon BIR
RING
Coiled coil
CARD
UBA
UBC
NACHT LRR
Fig. 1. The human IAP protein family. Human IAP proteins contain one or three baculovirus IAP repeat (BIR) domains. Several IAP family members possess RING (really interesting new gene) and UBA (ubiquitin-associated) domains. The c-IAP1 and c-IAP2 proteins also each contain a caspase recruitment domain (CARD). Survivin contains a coiled-coil domain; NAIP has NACHT (domain present in NAIP, CIITA, HET-E, TP1) and leucine-rich repeat (LRR) domains; Apollon possesses a ubiquitin conjugating (UBC) domain.
pathways converge at the level of activation of caspases, cysteine-dependent aspartyl-specific proteases that are critical for the execution of programmed cell death [19]. XIAP can directly bind to and potently inhibit caspase-3, caspase-7, and caspase-9 [20]. Inhibition of different classes of caspases by XIAP is mediated by an elegant binding scheme. Structural studies have revealed that XIAP inhibits caspases-3 and -7 by preventing substrate entry and catalysis via binding of an XIAP linker region, located just upstream of its BIR2 domain, to the caspase active sites [7]. Additionally, a surface peptide-binding groove of the BIR2 domain of XIAP binds to the processed amino-terminus of the small subunit of caspase-3, which is exposed upon proteolytic processing of caspase-3 [21]. Inhibition of caspase-9 is accomplished through two separate interactions within the XIAP BIR3 domain; the peptide-binding groove of BIR3 interacts with the amino-terminus of the small subunit of caspase-9, while another region of BIR3 binds to the caspase-9 homodimerization interface, thereby preventing caspase-9 dimerization and activation [22,23]. Potent inhibition of caspases by XIAP can be counteracted by the mitochondrial protein SMAC (second mitochondria-derived activator of caspases)/DIABLO (direct IAP-binding protein with low pI) [24,25]. Upon apoptotic signaling SMAC is released from mitochondria into the cytosol where it can bind XIAP and abrogate its caspaseinhibitory activity [24–26] (Fig. 2). SMAC contains a fourresidue long highly conserved IAP-binding motif (IBM; AV-P-I), that is exposed at the amino-terminus of the mature processed protein and competes with caspases for binding to the same surface peptide-binding grooves in the BIR domains of IAP proteins [5]. No other human IAP proteins examined, besides XIAP, have been proven to be potent physiological inhibitors of caspases [27–29]. However c-
IAP1, c-IAP2 and ML-IAP are each capable of binding to SMAC and effectively sequestering it away from XIAP, allowing XIAP to inhibit caspases and ultimately block apoptosis [28,30]. Additionally, c-IAP1, c-IAP2, XIAP, MLIAP, and Apollon are able to target caspases and SMAC for proteasomal degradation via their activity as E3 ubiquitin ligases [8,31,32]. Cellular IAP proteins exert a major impact on survival signaling pathways by way of their E3 ligase activity. Tumor necrosis receptor-associated factor 2 (TRAF2), an adaptor protein that functions in both canonical and noncanonical nuclear factor B (NF-jB) signaling pathways, interacts with c-IAP1 and c-IAP2 and recruits them to tumor necrosis factor (TNF) receptor complexes [5,18]. In the NF-jB canonical pathway c-IAP1 and c-IAP2 promote activation of signaling by their ubiquitination of receptor interacting protein (RIP1) (Fig. 3) [33–36]. However, in noncanonical NF-jB signaling, c-IAP proteins have been identified as the E3 ligases responsible for the ubiquitination and subsequent degradation of NF-jB-inducing kinase (NIK), and thus serve as negative regulators of this signaling pathway [37,38] (Fig. 3). Also, c-IAP1 has been shown to potentiate the activity of the oncogene Myc by promoting ubiquitination and proteasomal degradation of the Myc inhibitory protein, Mad1 [39]. The smallest, single BIR-containing, IAP protein survivin is primarily involved in cell division, not apoptosis. Transcription of survivin is upregulated during the G2M phase of the cell cycle and survivin controls cell division via its interactions with proteins of the chromosomal passenger complex (CPC) [40,41]. Likewise, recent studies suggest that Apollon functions mainly in cell division, and may potentially cooperate with survivin during cytokinesis [42]. NAIP, the first-discovered human member of the IAP protein family, is capable of preventing apoptosis provoked
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Apo2L/FasL
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Caspase-3/7 Active Caspase-3/7
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Fig. 2. The intrinsic and extrinsic apoptotic pathways. Programmed cell death is initiated in the intrinsic pathway by irradiation, growth factor withdrawal, or chemotherapeutic agents. Following neutralization of the anti-apoptotic proteins Bcl-2, Bcl-xL, and Mcl-1 and disruption of the mitochondrial membrane potential, cytochrome c and SMAC are released from the mitochondria into the cytoplasm. This leads to activation of caspase-9, subsequent activation of caspases-3 and -7, and ultimately cell death. Apoptotic signaling through the extrinsic pathway is triggered by binding of death ligands, such as TNFa and FasL, to their cognate death receptors, in this case TNF-R1 and Fas, respectively, which results in recruitment of the adaptor protein FADD and caspase-8. This leads to the activation of caspase-8, then caspases-3 and -7, and finally apoptosis. XIAP can inhibit caspases-3, -7, and -9; however, SMAC can bind to XIAP and prevent XIAP-mediated inhibition of caspases. ML-IAP, c-IAP1, and c-IAP2 can sequester SMAC away from XIAP, thus preventing its pro-apoptotic activity.
by a variety of apoptotic stimuli [16,43]. However, NAIP is generally not considered to be a true inhibitor of apoptosis. Rather, NAIP’s predominant role is probably in innate immunity where it mediates the host defense against intracellular pathogens [44,45]. ILP2, a tissue-specific homologue of XIAP, is inherently unstable and has not yet been demonstrated to inhibit apoptosis under physiological conditions [46].
3. Negative regulators of IAP proteins A subset of IAP-binding partners operates as endogenous inhibitors of IAP proteins, contributing to the finetuned balance between anti- and pro-apoptotic signaling in cells. As discussed in the previous section, SMAC is an endogenous IAP antagonist that binds to the BIR domains of IAP proteins via a conserved IAP-binding motif. Similarly, human High temperature requirement protein A2 (HtrA2/Omi) is a protein whose mature processed form is released from the mitochondria upon apoptotic signaling,
binds to IAP BIR domains via its IBM, and blocks IAP-mediated inhibition of cell death [47,48]. Additionally, HtrA2/ Omi possesses serine protease activity that contributes to its pro-apoptotic role [47,48]. Of note, both the IBM sequence and the mechanism of IAP regulation is conserved in the Drosophila IAP antagonists Reaper, Hid, Grim, and Sickle [49]. Several other BIR domains-binding proteins were identified through genomic screens (i.e. Nipsap or Nsp4, leucine-rich pentatricopeptide repeat motif-containing protein or LRPPR, 3 hydroxyisobutyrate dehydrogenase or 3HB) [50]. However, their functional significance in regulation of IAP-mediated inhibition of cell death is not yet apparent. XIAP-associated factor 1 (XAF1) was discovered in a yeast-two-hybrid screen for XIAP-interacting proteins, and acts as an endogenous inhibitor of XIAP [51]. XAF1 is a nuclear protein that has been shown to sequester XIAP in the nucleus, thus preventing XIAP-mediated inhibition of caspases in the cytosol [51]. Also XAF1 has been reported to interact with c-IAP1/2, ML-IAP, ILP2 and NAIP but not survivin, although a XIAP–XAF1 complex can indi-
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CD40L, TWEAK
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UbUb 48 Ub P I•B
P p100 RelB
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Fig. 3. Canonical and noncanonical NF-jB pathways. NF-jB signaling occurs via canonical and noncanonical pathways. Signaling through the TNF-R1 complex activates the canonical pathway, wherein binding of TNFa to TNF-R1 triggers recruitment of the adaptor protein TRADD, which in turn leads to the recruitment of TRAF2, RIP1, c-IAP1 and c-IAP2. RIP1 is then subject to c-IAP1/2-mediated ubiquitination by a variety of polyubiquitin linkages including K63 linkage. This modification facilitates assembly of the RIP1-associated kinase complexes, TAK1/TABs and IKK, leading to the phosphorylation and proteasomal degradation of IjB that enables NF-jB dimers to translocate to the nucleus and induce gene expression. Other receptors, such as FN14 or CD40R, can activate the noncanonical NF-jB signaling pathway. In this pathway c-IAP1/2 are recruited to receptor complexes by TRAF2, where they function as E3 ligases to promote K48-linked polyubiquitination and proteasomal degradation of NIK, and thus negatively regulate noncanonical NF-jB signaling.
rectly promote the proteasomal degradation of survivin [52]. Despite a lack of any recognizable IBM, XAF1 interacts with the BIR domains of IAP proteins; the exact mechanism of XAF1 IAP-antagonist activity and how the XIAP–XAF1 interaction is regulated is not known at present [53,54]. 4. IAP proteins in cancer Multiple lines of evidence have proven that IAP proteins are involved in cancer and other human malignancies. Firstly, a number of studies have demonstrated that elevated expression levels of IAP proteins, particularly cIAP1/2 and XIAP, in a number of tumor types correlates with a poor prognosis [5]. Survivin expression is undetectable in the majority of adult tissues, however, it is highly expressed in most human tumors [41]. Likewise, ML-IAP is not expressed in most normal human tissues but is frequently expressed at high levels in melanomas, bladder, and kidney cancers [55–59]. Additionally, expression of ML-IAP in melanomas is regulated by the lineage survival oncogene microphthalmia-associated transcription factor
(MITF), suggesting that the anti-apoptotic activity of MLIAP contributes to the pro-survival properties of MITF in melanoma progression [60]. Secondly, a number of animal and in vitro studies have further explored and illuminated the oncogenic potential of IAP proteins. In tumor cells down-regulation of XIAP expression, either by RNA interference or antisense oligonucleotides, results in stimulation of apoptosis and sensitization to gamma-irradiationand chemotherapeutic-induced apoptosis, both in vitro and in vivo [61–64]. Likewise, down-regulation of c-IAP1, ML-IAP, or survivin leads to activation of apoptotic pathways and increased sensitivity to cell death stimuli, such as chemotherapeutic agents and death receptors [5,41]. Lastly, direct genetic data established that c-IAP1/2 are potential pro-oncogenes. The chromosomal region 11q21– q23 containing c-IAP1 and c-IAP2 is subject to chromosomal amplification in esophageal squamous cell carcinomas, renal cell carcinomas, glioblastomas, gastric carcinomas, non-small cell lung carcinomas and other tumor types [5,18]. In murine tumors the syntenic region encompassing the c-IAP1 and c-IAP2 genes is also
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amplified, and ectopic overexpression of c-IAP1 in mouse models has been demonstrated to lead to tumor growth and hepatoma formation [65]. More genetic evidence comes from studies of an extranodal non-Hodgkin lymphoma, termed MALT lymphoma, where in around 50% of the cases surveyed the t(11,18)(q21;q21) translocation leads to a fusion of the BIR domains of c-IAP2 with the carboxy terminus of the paracaspase/MALT1 (mucosa-associated lymphoid tissue protein) [66–69]. The resultant c-IAP2:MALT1 fusion protein promotes constitutive activation of the NF-jB pathway, leading to increased pro-survival and inflammatory pathway signaling, as well as greater resistance to chemotherapeutic anti-tumor agents [70–72].
5. IAP proteins as targets in cancer therapy The significant problem of acquired chemotherapeutic resistance in tumor cells is a major concern in cancer therapy and targeting IAP proteins presents a potential therapeutic avenue to combat this challenge. A number of strategies to target IAP proteins in cancer are being explored. Herein the focus will center on the generation of reagents that mimic the amino-terminus of mature SMAC, the endogenous IAP antagonist. SMAC mimetics, including both SMAC derived peptides and small molecule antagonists, disrupt IAP:caspase and IAP:SMAC interactions, and stimulate cell death [5,73]. Additionally, work from Fulda et al., and other groups, demonstrated that SMAC-based peptides could significantly sensitize tumor cell lines to apoptosis induced by chemotherapeutics and death receptor agonists [74–77]. The first wave of small-molecule IAP antagonist were ‘monomeric’ compounds (Fig. 4) that bind to the BIR3 domains of XIAP, c-IAP1 and c-IAP2, and to the single BIR domain of ML-IAP [30,78–81]. Subsequently, ‘dimeric’ compounds (Fig. 4) were identified, initially by the serendipitous discovery of the bivalent Smac mimetic Compound 3, and later through an intentional structure-based design [78,82]. Several different binding assays indicated that bivalent compounds had higher affinity for full-length and BIR2–BIR3 containing IAP constructs compared to monovalent IAP antagonists, suggesting a two-site binding model [37,83,84]. In addition, analytical ultracentrifugation and gel filtration indicated that the bivalent antagonists induced dimerization of c-IAP1 BIR2–BIR3 and XIAP BIR3-only constructs, but not of an XIAP BIR2–BIR3 construct [37,83,84]. Bivalent IAP antagonists are extremely potent antagonists of IAPmediated anti-apoptotic activity [37,82,84]. This increased potency can be partly explained by their capacity to induce c-IAP dimerization, leading to more pronounced degradation of c-IAP1 and c-IAP2 [37]. But more importantly, the ability of bivalent IAP antagonists to engage BIR2 and BIR3 of XIAP at the same time results in a pronounced abrogation of XIAP-mediated caspase inhibition [85,86]. This strong caspase-3/7 activation is probably the major reason for the superior pro-apoptotic and anti-tumor activity of bivalent antagonists in comparison to monovalent compounds that can bind only one BIR domain at a time. Unexpectedly, studies from our group and others found that the ability of small-molecule IAP antagonists to induce
apoptosis relies largely on their induction of c-IAP1/2 autoubiquitination and proteasomal degradation, which in turn leads to the activation of NF-jB pathways and caspase-8dependent apoptosis in tumor cells [34,37,38,80,87,88]. IAP antagonist-induced activation of both the canonical and noncanonical NF-jB pathways leads to increased expression of the NF-jB responsive gene TNFa, which in the absence of c-IAP proteins promotes apoptosis by binding to TNF-R1, triggering TNFR-mediated signaling and activating caspase-8 [37,38,87] (Fig. 3). The application of TNF-blocking reagents or knockdown of TNF-R1 inhibited IAP antagonist-stimulated apoptosis, thus revealing that small-molecule IAP antagonist-induced cell death requires TNF signaling [37,38,80,87]. These studies provide strong evidence that targeting IAP proteins, namely cellular IAPs, with IAP antagonists results in heightened physiological TNF-receptor apoptotic signaling and apoptosis in tumor cells. By design IAP antagonists target a broad range of human IAP proteins. Nonetheless, there have been efforts towards developing IAP antagonists that selectively target either c-IAP1/2 or XIAP. A c-IAP-selective IAP antagonist has been engineered that possesses high selectivity for binding of c-IAP proteins over XIAP and can elicit c-IAP degradation, NF-jB pathway activation, and apoptosis in tumor cells (Fig. 4) [89]. However, in short- and long-term tumor cell survival assays the c-IAP-selective IAP antagonist was less effective at inducing cell death when compared with the pan-IAP antagonist, indicating that antagonism of both XIAP and c-IAP proteins is likely required for the most robust induction of apoptosis in cancer cells [89]. Two different strategies targeting XIAP:caspase3 interactions have been employed to selectively antagonize the anti-apoptotic activity of XIAP. One group discovered a small-molecule inhibitor of the XIAP:caspase-3 interaction by way of high-throughput biochemical screening, and showed that this XIAP specific antagonist could restore sensitivity to a particular apoptotic stimuli (Apo2L/ TRAIL) in a resistant tumor cell line [90]. Through a combinatorial chemistry library screen another group found a class of small molecules called polyphenylureas that can reverse XIAP-mediated inhibition of caspase-3, but not caspase-9, and promote anti-tumor activity in vitro and in vivo [91]. Collectively, these studies of c-IAP- and XIAP-selective antagonists have augmented our knowledge of the molecular mechanisms of IAP antagonism and further validated the applicability of targeting IAP proteins for cancer treatment. Small-molecule IAP antagonists and SMAC-based peptides have demonstrated efficacy in the treatment of breast cancer, non-small cell lung cancer, malignant glioma, and multiple myeloma models in vivo, suggesting that they may hold great promise for the treatment of cancer [5,78]. Currently, small-molecule IAP antagonists from Genentech, Inc., Novartis, Aegera Therapeutics/Human Genome Sciences, TetraLogic Pharmaceuticals, Ascenta Therapeutics, Joyant Pharmaceuticals, and possibly other institutions have entered, or are preparing to enter, clinical trials [78]. These Phase I trials will explore the safety and pharmacokinetcs of monovalent and bivalent IAP antagonists for the treatment of human malignancies. Preclinical
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H N
N H O
O
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N H
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Fig. 4. Structural representation of examples of ‘monomeric’ (MV1), ‘dimeric’ (BV6), c-IAP selective (CS3) and pan-IAP antagonists (PS1).
data suggest that the bivalent compounds could be more efficacious but due to their size, these reagents will likely be administered intravenously with less frequent dosing. Monovalent antagonists, on the other hand, could potentially be administered orally and more frequently, which may enable more continuous IAP antagonism. Hopefully, ongoing and forthcoming clinical trials will answer these questions and pave the way for future clinical investigations of IAP-regulated apoptotic pathways. An early report from the Phase I study of LCL161, an orally bioavaliable IAP antagonist, indicates that this treatment was well tolerated in cancer patients with no doselimiting toxicities reported [92]. Treatment with LCL161 also demonstrated target antagonism as shown by degradation of c-IAP1 protein 2 h post-dose and subsequent upregulation of circulating cytokines such as MCP-1 and IL-8 [92]. However, since the degradation of c-IAP1 protein can be expected in non-tumor tissues, as well as in responsive and nonresponsive malignancies, it is likely that cIAP1 degradation could serve as an indicator of IAP-antagonist activity, but not as a predictive marker. Therefore, it will be exceedingly important to identify the predictive marker(s) that would allow selection of the patient population(s) that will benefit the most from this therapeutic approach. Thus far, it is clear that TNFa is critical for the single-agent activity of IAP antagonists in cancer cells, but it is far less obvious how instrumental local, or systemic, TNFa will be for the anti-tumor activity of IAP-targeting compounds. In addition to showing single-agent anti-tumor activity in in vivo mouse models, IAP antagonists also exhibit synergy in combination with a number of pro-apoptotic and anti-proliferative agents [86,93–99]. IAP antagonists enhanced apoptosis induced by pro-apoptotic receptor ago-
nists, such as TRAIL/Apo2L, FasL, and anti-DR5 antibody in various human cancer cell lines, and augmented TRAIL/Apo2L’s or anti-DR5’s anti-tumor activity in a mouse xenograft model [86,95,97,99]. Additionally, IAP antagonists were demonstrated to synergize with well-established cytotoxic chemotherapeutics in human prostrate cancer and non-small cell lung cancer (NSCLC) cells, as well as in mouse xenograft and transgenic models of pancreatic cancer [93,94,98]. Future clinical trials designed to test these combinations, and diagnostic efforts aimed at identifying treatment-suitable population(s), should provide novel therapeutic opportunities for cancer patients. In conclusion, due to their potent anti-apoptotic activity and elevated expression in many tumor types, the IAP proteins have proven to be promising targets for therapeutic intervention in cancer. Continued research efforts to elucidate the myriad aspects of IAP functions within apoptosis, signal transduction pathways, protein turnover, and cell division harbor the potential to lead to new therapeutic strategies.
Conflict of interest Both authors are employees of Genentech, Inc.
Acknowledgments The authors thank Kurt Deshayes, Wayne J. Fairbrother, Eugene Varfolomeev and Tatiana Goncharov for helpful discussion, critical reading of the manuscript and help with the figure design. Both authors are employees of Genentech, Inc.
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