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TRAIL Signaling and Synergy Mechanisms Used in TRAIL-Based Combination Therapies

Christian T. Hellwig and Markus Rehm
Christian T. Hellwig
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Markus Rehm
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DOI: 10.1158/1535-7163.MCT-11-0434 Published January 2012
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Abstract

TRAIL and agonistic antibodies raised against TRAIL death receptors are highly promising new anticancer agents. In this brief review, we describe the recent advances in the molecular understanding of TRAIL signaling and the progress made in using TRAIL or agonistic antibodies clinically in mono- and combination therapies. Synergies have been reported in various scenarios of TRAIL-based multidrug treatments, and these can be used to potentiate the efficacy of therapies targeting TRAIL death receptors. We pay particular attention to structure the current knowledge on the diverse molecular mechanisms that are thought to give rise to these synergies and describe how different signaling features evoking synergies can be associated with distinct classes of drugs used in TRAIL-based combination treatments. Mol Cancer Ther; 11(1); 3–13. ©2012 AACR.

Introduction

Since the discovery of members of the TNF family and their so-called death receptors, the possibility of a new avenue for apoptosis-inducing cancer therapies has emerged. The death ligand–dependent extrinsic apoptotic pathway can induce apoptosis independent of the transcription factor p53 and, therefore, can circumvent the apoptosis resistance acquired by many tumors through loss-of-function mutations in this tumor suppressor. However, TNFα and agonistic antibodies activating the Fas receptor were found to be highly cytotoxic toward primary hepatocytes and other nontransformed cells when applied at clinically relevant concentrations (1, 2). In contrast, soluble TRAIL as well as leucine zipper–trimerized TRAIL potently induce apoptosis in a range of cancer cell lines, can inhibit tumor xenografts in mice, and were found to be of very low systemic toxicity in mice and nonhuman primates (3, 4). These findings sparked tremendous interest in exploring the potential of TRAIL as an anticancer therapeutic for a broad range of human malignant neoplasms. In this review, we briefly describe the key signaling events during TRAIL-induced apoptosis initiation, give a short overview on the status of TRAIL-based clinical research and trials, and describe the mechanisms of signaling processes that evoke synergistic apoptosis responses in TRAIL-based combination treatments.

TRAIL

Endogenous TRAIL is expressed as a 281–amino acid type II trans-membrane protein, which is anchored to the plasma membrane and presented on the cell surface. TRAIL was independently identified by Wiley and colleagues and Pitti and colleagues in 1995 and 1996, respectively, and sequence alignments indicated its close relation to other death ligands, with highest sequence similarities reported for Fas ligand (FasL; refs. 5, 6). TRAIL is expressed by natural killer cells, which, following the establishment of cell–cell contacts, can induce TRAIL-dependent apoptosis in target cells (7). Physiologically, the TRAIL-signaling system was shown to be essential for immune surveillance, for shaping the immune system through regulating T-helper cell 1 versus T-helper cell 2 as well as “helpless” CD8+ T-cell numbers, and for the suppression of spontaneous tumor formation (8–10).

TRAIL-Induced Apoptosis Initiation: Signaling through Death and Decoy Receptors

TRAIL induces apoptosis through ligation with its cognate death receptors TRAIL-R1 (also known as DR4) and TRAIL-R2 (DR5; Fig. 1; refs. 11–13), and the trimerization of TRAIL around a central zinc atom via cysteine230 is essential for its apoptotic potential (14, 15). TRAIL binding is followed by receptor trimerization, and groups of trimerized death receptors can further cluster together to form bigger aggregates. These aggregates predominantly accumulate in lipid raft microdomains in the plasma membrane (16). The molecular composition of the receptor trimers has been controversially discussed, and it has not been fully resolved whether, at physiologic conditions, exclusively homotypic interactions or also heterocomplexes can be observed (17–20). Following trimerization of TRAIL-R1 or TRAIL-R2, the adaptor protein Fas-associated death domain containing protein (FADD) can bind to the intracellular death domains of the receptors and promote the recruitment and activation of initiator caspase-8 within the death-inducing signaling complex (DISC; Fig. 1D). In most cells, caspase-8 then initiates apoptosis through Bid cleavage and the mitochondrial apoptosis pathway (Fig. 1E). Both the formation of the caspase-activating DISC, as well as the subsequent signaling network leading to apoptosis execution, can be modulated through a multitude of complex regulatory processes (21, 22).

Figure 1.
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Figure 1.

Simplified overview of TRAIL-mediated apoptosis signaling. A, trimers of TRAIL can bind to the extracellular regions of TRAIL-R1, TRAIL-R2, TRAIL-R3, and TRAIL-R4. The proapoptotic TRAIL-R1 and TRAIL-R2 comprise cytosolic regions, including a death domain (DD), which is missing in the antiapoptotic TRAIL-R3 and TRAIL-R4. TRAIL-R3 also lacks the transmembrane region. Osteoprotegerin can serve as a soluble decoy receptor. B, antiapoptotic TRAIL-R3 forms homotrimers following TRAIL binding. TRAIL-R4 can also form heterotrimers with TRAIL-R1 and/or TRAIL-R2. These receptor clusters are unable to transduce the TRAIL signal further and, therefore, act as antiapoptotic TRAIL scavengers. C, TRAIL-R1 or TRAIL-R2 can recruit FADD to form the DISC. Procaspase-8 and cFLIP (a catalytically inactive caspase-8 homolog) compete for FADD binding via their death effector domains (DED). Procaspase-8 consists of a DED-containing prodomain, as well as large and small catalytic subunits. Heterodimers of caspase-8 and the long splice variant cFLIP have a very limited substrate repertoire and, in most cases, cannot transduce the apoptosis signal. The short splice variant of cFLIP (not shown) forms inactive heterodimers with caspase-8. D, induced proximity of 2 procaspase-8 zymogens at the DISC results in autocatalytic cleavage of the linkers between the procaspase-8 subunits and caspase-8 activation. Active caspase-8 either resides at the DISC or, once fully processed, can be released into the cytosol. E, active caspase-8 cleaves Bid, inducing the mitochondrial apoptosis pathway, or directly activates effector caspase-3. XIAP suppresses caspase-9 and caspase-3 activity.

Additional TRAIL receptors, which are incapable of transducing the death signal because they lack a functional intracellular death domain, have been identified. These receptors are TRAIL-R3, TRAIL-R4, and osteoprotegerin (22). TRAIL-R3 and TRAIL-R4 are alternatively also referred to as decoy receptors 1 and 2 (DcR1, DcR2). TRAIL-R4 (DcR2) bears huge similarities to TRAIL-R1 and TRAIL-R2; however, it contains only a truncated cytosolic death domain (Fig. 1A; ref. 23). TRAIL-R3 (DcR1) consists of an extracellular cysteine-rich structure that resembles the proapoptotic TRAIL receptors and is associated with the plasma membrane through a COOH-terminal glycosyl-phosphatidylinositol anchor (Fig. 1A; refs. 11, 24). It is still highly debated whether overexpression of TRAIL-R3 or TRAIL-R4 correlates with cellular apoptosis resistance upon TRAIL exposure, and high expression levels are rarely found naturally in isolated cancer cell lines. The exact molecular details of how decoy receptors inhibit TRAIL-induced apoptosis in addition to their obvious role as TRAIL scavengers are not fully resolved and may differ between TRAIL-R3 and TRAIL-R4. For example, it was reported that TRAIL-R3 exclusively forms homotrimers upon TRAIL binding, whereas TRAIL-R4 may also aggregate into heterotrimers with activated TRAIL-R1 and TRAIL-R2 (Fig. 1B; ref. 25). Such heterotrimers are incapable of forming a functional DISC required for apoptosis initiation. Relatively little is known about osteoprotegerin, the fifth receptor capable of TRAIL binding. Osteoprotegerin negatively regulates osteoclastogenesis and is largely secreted as a soluble protein that might act as a scavenger for soluble TRAIL (26). Uncertainties remain about the molecular mechanisms of death and decoy receptor interaction, and it remains to be conclusively shown whether the relative abundance of death versus decoy receptors could serve to indicate cellular susceptibility to TRAIL-induced apoptosis.

Preclinical Evidence for the Anticancer Potential of TRAIL and Its Tolerability

TRAIL treatment strategies largely build on soluble variants of recombinant human TRAIL (rhTRAIL, a 60-kDa homotrimer TRAIL protein without its membrane anchor), as well as on monoclonal agonistic antibodies, which specifically target death receptor TRAIL-R1 or TRAIL-R2, thereby potentially circumventing decoy receptor–mediated resistance, and which in addition have the benefit of a significantly longer plasma half-life (27, 28). Additionally, to increase the local concentration and cancer cell–directed cytotoxicity of TRAIL, fusion proteins have been designed to translocate TRAIL to specific tissues or cells, for example, the epidermal growth factor receptor (EGFR)–selective delivery of soluble TRAIL, combined with an EGFR-targeting antibody fragment (29). Soluble TRAIL fused to a melanoma-associated chondroitin sulfate proteoglycan (MCSP)–specific antibody fragment combines inhibition of MCSP tumorigenic signaling with TRAIL-mediated apoptosis induction in melanoma cells (30). A multitude of studies using models of human tumor xenografts in mice showed a high anticancer activity of TRAIL or receptor-specific ligands in vivo, and TRAIL efficacy can be potentiated in combination treatments with kinase and proteasome inhibitors, genotoxic drugs, histone deacetylase inhibitors, and others drugs (20, 31).

It has frequently been debated whether TRAIL can be cytotoxic to untransformed cells in vivo. In contrast to the high tolerability of TRAIL found in the seminal studies of Ashkenazi and colleagues and Walczak and colleagues (3, 4), other studies reported toxicities of TRAIL in isolated human hepatocytes (32, 33) and human brain tissue (34). However, significant TRAIL hepatotoxicities seem to be restricted to ex vivo cultures of primary liver cells or to highly aggregated TRAIL variants carrying flag or polyhistidine tags (35, 36). In contrast, rhTRAIL, as well as leucine or isoleucine zipper variants of TRAIL, was shown to be well tolerated in animal models. This finding is in stark contrast to the generally high hepatotoxicities that were reported for death ligands FasL and TNFα (3, 4). As a note of caution, however, it was shown that liver steatosis or hepatitis C infection can increase human hepatocyte sensitivity toward TRAIL (37), suggesting that patients from these risk groups should be excluded from TRAIL-based therapies.

TRAIL in Clinical Trials: Monotherapies

Soluble rhTRAIL (also named dulanermin), the TRAIL-R1–targeting monoclonal agonistic antibody mapatumumab, and the TRAIL-R2–targeting monoclonal agonistic antibodies lexatumumab, conatumumab, tigatuzumab, and DAB4 (also named PRO95780) have entered clinical studies. A large number of phase I and phase II clinical trials have been undertaken with these agents by now or are still ongoing, either as monotherapy or in combination with other chemotherapeutic drugs. These trials target a wide range of both solid and nonsolid malignant neoplasms.

Toxicity studies as part of an rhTRAIL phase I trial provided encouraging results. In a dose-escalating monotherapy in patients with advanced cancers, rhTRAIL was well tolerated at serum concentrations that were shown to be effective against cancer cells in preclinical models (38). Similarly, TRAIL-R1–specific mapatumumab seems to be well tolerated, and in a phase II study in patients with relapsed or refractory non-Hodgkin lymphoma, approximately one third of all patients responded to mapatumumab (28, 39, 40). In a phase II clinical trial, mapatumumab was well tolerated in patients with colorectal cancer (41). Lexatumumab, conatumumab, tigatuzumab, PRO95780, and other TRAIL-R2–targeting antibodies, likewise, were investigated in phase I and II clinical trials (42–44). Like mapatumumab, these antibodies only caused low-to-moderate side effects in a small number of patients. Several patients showed partial responses or attenuated disease progression when treated with TRAIL-R2–targeting antibodies (45, 46). In general, TRAIL and TRAIL receptor–binding antibodies, therefore, seem to be well tolerated, and only a few cases of adverse responses have been documented. Furthermore, promising results in patients with advanced or refractory cancers underline the therapeutic potential of TRAIL receptor–targeting molecules. However, as a caveat, signaling through TRAIL death receptors may also induce antiapoptotic responses and proliferation signaling. This alternative response was shown to require the activation of kinases, such as RIP1, IKK, c-jun-NH2-kinase, or p38 in signaling complexes secondary to the DISC (47) and to induce transcription-dependent prosurvival responses that attenuate apoptosis signaling. Indeed, subpopulations of primary cells isolated from children with acute leukemia showed increased proliferation rates following TRAIL treatment (48). These prosurvival responses may, therefore, limit the usability of TRAIL in monotherapies.

TRAIL in Clinical Trials: Combination Therapies

Cancers like melanoma, leukemia, multiple myeloma, breast, bladder, prostate, renal, colon, and others would be expected to be largely TRAIL sensitive judging on the basis of preclinical drug response data. However, cases of TRAIL resistance are frequently being observed and often could be associated with the overexpression of antiapoptotic proteins or the low expression of TRAIL receptors. An attractive and preclinically successful strategy, therefore, is to identify combination treatments that sensitize otherwise resistant cancers to TRAIL. Although this strategy holds risks because of the potential sensitization of nontransformed cells to the treatment, initial results are very promising. In a phase Ib clinical study to determine safety, pharmacokinetics, and maximum dose tolerance levels, patients with non–small cell lung cancer were treated with rhTRAIL (dulanermin), combined with paclitaxel, carboplatin, and bevacizumab. No dose-limiting toxicity was observed, and the treatment was well tolerated, with 1 complete response and a high percentage of partial responses observed (49). Other early phase Ib trials assessing combination treatments with mapatumumab and paclitaxel or carboplatin, as well as mapatumumab together with gemcitabine or cisplatin, in patients with advanced solid tumors reported high tolerability of mapatumumab (50, 51). By now, many more additional phase I and II clinical trials have been conducted or are still ongoing in other cancer types and using additional U.S. Food and Drug Administration–approved drugs, such as kinase inhibitors, proteasome inhibitors, histone deacetylase inhibitors, or genotoxic drugs, in combination with TRAIL (Table 1; ref. 45). Even though cases of adverse effects and toxicities were reported, overall, TRAIL combination therapies seem to be remarkably well tolerated. Still, outstanding results from ongoing phase II clinical trials will soon allow assessment of whether patients may benefit from such alternative treatment regimes and whether patient responses are indicative of multidrug synergies that were reported in vitro. The mechanisms bringing about synergistic multidrug responses are very complex. However, significant progress in understanding the underlying signaling cross-talk has been made in recent years, as outlined in the following discussion.

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Table 1.

Modulation of TRAIL-mediated apoptosis through combination treatments: clinical trials

Drug Classes and Their Synergy Mechanisms in TRAIL Combination Treatments

Synergistic effects of chemotherapeutics in combination with TRAIL have been reported for various classes of drugs. In general, synergies arise from nonlinear cross-potentiation of drug effects. In the framework of apoptosis signaling, such potentiation may arise from the (often p53-dependent) transcriptional upregulation of proapoptotic proteins, from their accumulation due to impaired protein degradation, from alterations in regulatory posttranslational protein modifications, or from combinations of these processes. In the following paragraphs, we discuss the synergy mechanisms exerted by different drug classes. Related to this discussion, an overview of clinical trials aiming to use drug synergies in TRAIL-based combination treatments is provided in Table 1. Information on additional novel and promising cotreatment strategies that are still at the preclinical stage is provided in Supplementary Table S1.

Different genotoxic drugs have been suggested to enhance TRAIL signaling and its anticancer potential, with 5-fluorouracil and cisplatin having been studied most intensely. A typical stress response to genotoxic monotherapies is the transcriptional induction of BH3-only proteins, such as Puma, which is a potent inducer of apoptosis through the mitochondrial pathway (52). Such responses may synergistically complement the BH3-only protein Bid, which is cleaved and activated by caspase-8 in response to TRAIL. In this respect, similar synergy mechanisms would be relevant in cotreatment scenarios based on synthetic BH3-only protein mimetics, such as AT-101 (a gossypol derivate), ABT-263, ABT-737, and GX-15-070 (obatoclax; ref. 53). These novel drugs are already undergoing evaluation in monotherapy trials and may hold great potential for future combination treatments. However, synergies achieved with genotoxic drugs may also arise from upstream modulation of TRAIL signaling. For example, 5-fluorouracil can prime TRAIL-resistant hepatocellular carcinoma cells to apoptosis, at least partially, through the downregulation of the inactive caspase-8 homolog cFlip (Fig. 1C) and through the parallel upregulation of TRAIL-R2 at physiologically relevant doses (54). Importantly, cytotoxicity to normal cells seems to be limited to acceptable levels in this scenario (54). Similar scenarios of death receptor upregulation or cFlip downregulation were also reported in response to other genotoxic drugs, as well as to ionizing irradiation and epigenetic inhibitors, such as histone deacetylase inhibitors (55, 56). Also IFNs, which are frequently used in hematologic cancer therapy, were shown to potently promote TRAIL-induced apoptosis through evoking transcriptional responses. For example, IFN-α exposure can increase TRAIL and TRAIL-R2 expression in human hepatocellular carcinoma cells (57, 58), whereas IFN-γ can reduce cFlip protein levels (59).

Prolonged proteasome inhibition induces the expression and accumulation of BH3-only proteins, such as Bim, Bik, Puma, and Noxa (60), which leads to synergy mechanisms like those described above for genotoxic drugs. Furthermore, TRAIL-induced NF-κB activation and prosurvival signaling can be limited by proteasome inhibition because the degradation of NF-κB inhibitor IκBα is prevented (23, 61). Maybe more importantly, proteasome inhibition can lead to the direct accumulation of proteins that promote TRAIL-induced apoptosis. An accumulation of both TRAIL-R1 and TRAIL-R2 was described in response to proteasome inhibition in various cancers (62–64), potentially resulting in more efficient DISC formation and caspase activation upon TRAIL addition. The consequences arising from a general inhibition of protein degradation are naturally complex, due to the global disturbance of relative protein abundances in addition to active transcriptional stress responses. Attributing synergies in TRAIL and/or proteasome inhibitor cotreatments to the modulation of single proteins or processes, as proposed in several studies, therefore likely presents an oversimplification of the underlying molecular mechanisms that enhance TRAIL responsiveness. Nevertheless, the fact that proteasome inhibition can promote proapoptotic signaling, at least partially, independent of protein neosynthesis makes proteasome inhibitors particularly attractive for the treatment of cancers that present with deficiencies in transcriptional proapoptotic responses, as can arise from loss-of-function mutations in tumor suppressor p53.

Transcription- or p53-independent synergisms of chemotherapeutics and TRAIL can also be achieved by targeting posttranslational protein modifications such as phosphorylation patterns. For example, inhibiting protein kinase CK2 impairs Bid phosphorylation and enhances Bid cleavage by caspase-8 (65, 66) and may be an attractive cotreatment strategy if outstanding safety tests yield satisfying results. Procaspase-8 itself can be phosphorylated by Src kinase, which impairs its binding to and activation at the DISC (67). In addition, formation of the DISC can be modulated upstream of caspase-8 recruitment through mitogen-activated protein kinases (MAPK; ref. 68). Furthermore, protein kinase C activity limits FADD recruitment into the DISC (69). Kinase inhibition can also directly or indirectly induce transcriptional responses, adding further complexity. For example, inhibiting phosphoinositide 3-kinase (PI3K)/AKT signaling by perifosine can restore TRAIL sensitivity in acute myelogenous leukemia through a p53-independent TRAIL-R2 upregulation and a concomitant cFlip and X-linked inhibitor-of-apoptosis protein (XIAP) downregulation (70). Multitarget kinase inhibitors, such as sorafenib, may therefore hold great potential in enhancing cancer cell responsiveness and are currently being investigated in combination treatments with TRAIL in phase I clinical trials (45). Furthermore, additional posttranslational modifications of the death receptors, such as palmitoylation, nitrosylation, and glycosylation, have been reported, and these modifications can influence cellular sensitivity toward TRAIL (22). Whether these modifications can be therapeutically targeted and used is currently unknown.

Antagonists of inhibitor-of-apoptosis proteins, such as synthetic Smac peptides and Smac mimetics, were shown to sensitize various cancer cell lines to TRAIL-induced apoptosis. In particular, antagonizing XIAP, the most potent inhibitor of executioner caspases, promotes the direct activation of caspase-3 by caspase-8 and results in efficient apoptosis execution (71, 72). Furthermore, Smac mimetics also bind to cellular IAP (cIAP)–1 and cIAP-2. As a consequence, cIAPs are rapidly degraded and cells may respond with secreting TNFα (73, 74). TNFα then may further enhance apoptosis by activating a parallel extrinsic apoptosis pathway that leads to caspase-8 activation. IAP inhibitors have been shown to synergistically kill pancreatic cancer cells in combination with the TRAIL-R1–targeting antibody mapatumumab, whereas the combined treatment with the TRAIL-R2–specific antibody lexatumumab was less efficient, indicating receptor-specific differences in synergy and susceptibility of certain cancers (75). Besides the requirement to better understand and use synergy mechanisms, means to predetermine differential sensitivity to either TRAIL-R1–or TRAIL-R2–transduced apoptosis will be paramount to case specifically identify the most effective treatment strategies in the future.

Conclusions

Experimental preclinical as well as clinical evidence shows that TRAIL has a high potential as a novel anticancer drug, both in monotherapies and in combination treatments (Table 1 and Supplementary Table S1). Given the comprehensive research activities currently focusing on identifying and deciphering the complex intracellular signaling cross-talk that evokes synergies in TRAIL combination treatments, we will soon better understand which conditions need to be fulfilled to more efficiently use the potential of different TRAIL-based treatment strategies. At this stage, TRAIL signaling is already one of the best-characterized apoptotic signaling pathways. In the coming years, this information may greatly assist in identifying potential biomarkers that will allow researchers to rationally predict tumor responsiveness to TRAIL-based therapies. This important, but still outstanding milestone, will need to be achieved before patient benefits can be maximized through appropriately tailored drug administration.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Grant Support

This work was supported by grants from Science Foundation Ireland (05/RFP/BIM056), the Health Research Board Ireland (RP/2006/258; RP/2008/7), and the Irish National Biophotonics and Imaging Platform funded under the Irish Higher Education Authority Programme for Third Level Institutions (HEA PRTLI) Cycle 4, cofunded by the Irish Government and the European Union “Investing in your future.”

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received June 10, 2011.
  • Revision received September 2, 2011.
  • Accepted September 5, 2011.
  • ©2012 American Association for Cancer Research.

References

  1. 1.↵
    1. Costelli P,
    2. Aoki P,
    3. Zingaro B,
    4. Carbó N,
    5. Reffo P,
    6. Lopez-Soriano FJ,
    7. et al.
    Mice lacking TNFalpha receptors 1 and 2 are resistant to death and fulminant liver injury induced by agonistic anti-Fas antibody. Cell Death Differ 2003;10:997–1004.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Ogasawara J,
    2. Watanabe-Fukunaga R,
    3. Adachi M,
    4. Matsuzawa A,
    5. Kasugai T,
    6. Kitamura Y,
    7. et al.
    Lethal effect of the anti-Fas antibody in mice. Nature 1993;364:806–9.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Walczak H,
    2. Miller RE,
    3. Ariail K,
    4. Gliniak B,
    5. Griffith TS,
    6. Kubin M,
    7. et al.
    Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 1999;5:157–63.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Ashkenazi A,
    2. Pai RC,
    3. Fong S,
    4. Leung S,
    5. Lawrence DA,
    6. Marsters SA,
    7. et al.
    Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999;104:155–62.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Wiley SR,
    2. Schooley K,
    3. Smolak PJ,
    4. Din WS,
    5. Huang CP,
    6. Nicholl JK,
    7. et al.
    Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995;3:673–82.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Pitti RM,
    2. Marsters SA,
    3. Ruppert S,
    4. Donahue CJ,
    5. Moore A,
    6. Ashkenazi A
    . Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996;271:12687–90.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Smyth MJ,
    2. Cretney E,
    3. Takeda K,
    4. Wiltrout RH,
    5. Sedger LM,
    6. Kayagaki N,
    7. et al.
    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. J Exp Med 2001;193:661–70.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Cretney E,
    2. Takeda K,
    3. Yagita H,
    4. Glaccum M,
    5. Peschon JJ,
    6. Smyth MJ
    . Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 2002;168:1356–61.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Janssen EM,
    2. Droin NM,
    3. Lemmens EE,
    4. Pinkoski MJ,
    5. Bensinger SJ,
    6. Ehst BD,
    7. et al.
    CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 2005;434:88–93.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Zhang XR,
    2. Zhang LY,
    3. Devadas S,
    4. Li L,
    5. Keegan AD,
    6. Shi YF
    . Reciprocal expression of TRAIL and CD95L in Th1 and Th2 cells: role of apoptosis in T helper subset differentiation. Cell Death Differ 2003;10:203–10.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. MacFarlane M,
    2. Ahmad M,
    3. Srinivasula SM,
    4. Fernandes-Alnemri T,
    5. Cohen GM,
    6. Alnemri ES
    . Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL. J Biol Chem 1997;272:25417–20.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Pan G,
    2. O'Rourke K,
    3. Chinnaiyan AM,
    4. Gentz R,
    5. Ebner R,
    6. Ni J,
    7. et al.
    The receptor for the cytotoxic ligand TRAIL. Science 1997;276:111–3.
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. Walczak H,
    2. Degli-Esposti MA,
    3. Johnson RS,
    4. Smolak PJ,
    5. Waugh JY,
    6. Boiani N,
    7. et al.
    TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J 1997;16:5386–97.
    OpenUrlAbstract
  14. 14.↵
    1. Bodmer JL,
    2. Meier P,
    3. Tschopp J,
    4. Schneider P
    . Cysteine 230 is essential for the structure and activity of the cytotoxic ligand TRAIL. J Biol Chem 2000;275:20632–7.
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. Hymowitz SG,
    2. O'Connell MP,
    3. Ultsch MH,
    4. Hurst A,
    5. Totpal K,
    6. Ashkenazi A,
    7. et al.
    A unique zinc-binding site revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL. Biochemistry 2000;39:633–40.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Song JH,
    2. Tse MC,
    3. Bellail A,
    4. Phuphanich S,
    5. Khuri F,
    6. Kneteman NM,
    7. et al.
    Lipid rafts and nonrafts mediate tumor necrosis factor related apoptosis-inducing ligand induced apoptotic and nonapoptotic signals in non small cell lung carcinoma cells. Cancer Res 2007;67:6946–55.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. Bin L,
    2. Thorburn J,
    3. Thomas LR,
    4. Clark PE,
    5. Humphreys R,
    6. Thorburn A
    . Tumor-derived mutations in the TRAIL receptor DR5 inhibit TRAIL signaling through the DR4 receptor by competing for ligand binding. J Biol Chem 2007;282:28189–94.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    1. Kischkel FC,
    2. Lawrence DA,
    3. Chuntharapai A,
    4. Schow P,
    5. Kim KJ,
    6. Ashkenazi A
    . Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 2000;12:611–20.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Tur V,
    2. van der Sloot AM,
    3. Reis CR,
    4. Szegezdi E,
    5. Cool RH,
    6. Samali A,
    7. et al.
    DR4-selective tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) variants obtained by structure-based design. J Biol Chem 2008;283:20560–8.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. van der Sloot AM,
    2. Tur V,
    3. Szegezdi E,
    4. Mullally MM,
    5. Cool RH,
    6. Samali A,
    7. et al.
    Designed tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the DR5 receptor. Proc Natl Acad Sci U S A 2006;103:8634–9.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Hellwig CT,
    2. Passante E,
    3. Rehm M
    . The molecular machinery regulating apoptosis signal transduction and its implication in human physiology and pathophysiologies. Curr Mol Med 2011;11:31–47.
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Pennarun B,
    2. Meijer A,
    3. de Vries EG,
    4. Kleibeuker JH,
    5. Kruyt F,
    6. de Jong S
    . Playing the DISC: turning on TRAIL death receptor-mediated apoptosis in cancer. Biochim Biophys Acta 2010;1805:123–40.
    OpenUrlPubMed
  23. 23.↵
    1. Degli-Esposti MA,
    2. Dougall WC,
    3. Smolak PJ,
    4. Waugh JY,
    5. Smith CA,
    6. Goodwin RG
    . The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 1997;7:813–20.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Sheridan JP,
    2. Marsters SA,
    3. Pitti RM,
    4. Gurney A,
    5. Skubatch M,
    6. Baldwin D,
    7. et al.
    Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997;277:818–21.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    1. Mérino D,
    2. Lalaoui N,
    3. Morizot A,
    4. Schneider P,
    5. Solary E,
    6. Micheau O
    . Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2. Mol Cell Biol 2006;26:7046–55.
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    1. Emery JG,
    2. McDonnell P,
    3. Burke MB,
    4. Deen KC,
    5. Lyn S,
    6. Silverman C,
    7. et al.
    Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998;273:14363–7.
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    1. Kelley SK,
    2. Harris LA,
    3. Xie D,
    4. Deforge L,
    5. Totpal K,
    6. Bussiere J,
    7. et al.
    Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety. J Pharmacol Exp Ther 2001;299:31–8.
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    1. Tolcher AW,
    2. Mita M,
    3. Meropol NJ,
    4. von Mehren M,
    5. Patnaik A,
    6. Padavic K,
    7. et al.
    Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1. J Clin Oncol 2007;25:1390–5.
    OpenUrlAbstract/FREE Full Text
  29. 29.↵
    1. Bremer E,
    2. de Bruyn M,
    3. Samplonius DF,
    4. Bijma T,
    5. ten Cate B,
    6. de Leij LF,
    7. et al.
    Targeted delivery of a designed sTRAIL mutant results in superior apoptotic activity towards EGFR-positive tumor cells. J Mol Med (Berl) 2008;86:909–24.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. de Bruyn M,
    2. Rybczynska AA,
    3. Wei Y,
    4. Schwenkert M,
    5. Fey GH,
    6. Dierckx RA,
    7. et al.
    Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP)-targeted delivery of soluble TRAIL potently inhibits melanoma outgrowth in vitro and in vivo. Mol Cancer 2010;9:301.
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. Johnstone RW,
    2. Frew AJ,
    3. Smyth MJ
    . The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer 2008;8:782–98.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Jo M,
    2. Kim TH,
    3. Seol DW,
    4. Esplen JE,
    5. Dorko K,
    6. Billiar TR,
    7. et al.
    Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med 2000;6:564–7.
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Mori E,
    2. Thomas M,
    3. Motoki K,
    4. Nakazawa K,
    5. Tahara T,
    6. Tomizuka K,
    7. et al.
    Human normal hepatocytes are susceptible to apoptosis signal mediated by both TRAIL-R1 and TRAIL-R2. Cell Death Differ 2004;11:203–7.
    OpenUrlCrossRefPubMed
  34. 34.↵
    1. Nitsch R,
    2. Bechmann I,
    3. Deisz RA,
    4. Haas D,
    5. Lehmann TN,
    6. Wendling U,
    7. et al.
    Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL). Lancet 2000;356:827–8.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. Lawrence D,
    2. Shahrokh Z,
    3. Marsters S,
    4. Achilles K,
    5. Shih D,
    6. Mounho B,
    7. et al.
    Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 2001;7:383–5.
    OpenUrlCrossRefPubMed
  36. 36.↵
    1. Qin J,
    2. Chaturvedi V,
    3. Bonish B,
    4. Nickoloff BJ
    . Avoiding premature apoptosis of normal epidermal cells. Nat Med 2001;7:385–6.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Volkmann X,
    2. Fischer U,
    3. Bahr MJ,
    4. Ott M,
    5. Lehner F,
    6. Macfarlane M,
    7. et al.
    Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver. Hepatology 2007;46:1498–508.
    OpenUrlCrossRefPubMed
  38. 38.↵
    1. Herbst RS,
    2. Eckhardt SG,
    3. Kurzrock R,
    4. Ebbinghaus S,
    5. O'Dwyer PJ,
    6. Gordon MS,
    7. et al.
    Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer. J Clin Oncol 2010;28:2839–46.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    1. Hotte SJ,
    2. Hirte HW,
    3. Chen EX,
    4. Siu LL,
    5. Le LH,
    6. Corey A,
    7. et al.
    A phase 1 study of mapatumumab (fully human monoclonal antibody to TRAIL-R1) in patients with advanced solid malignancies. Clin Cancer Res 2008;14:3450–5.
    OpenUrlAbstract/FREE Full Text
  40. 40.↵
    1. Younes A,
    2. Vose JM,
    3. Zelenetz AD,
    4. Smith MR,
    5. Burris HA,
    6. Ansell SM,
    7. et al.
    A Phase 1b/2 trial of mapatumumab in patients with relapsed/refractory non-Hodgkin's lymphoma. Br J Cancer 2010;103:1783–7.
    OpenUrlCrossRefPubMed
  41. 41.↵
    1. Trarbach T,
    2. Moehler M,
    3. Heinemann V,
    4. Köhne CH,
    5. Przyborek M,
    6. Schulz C,
    7. et al.
    Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer. Br J Cancer 2010;102:506–12.
    OpenUrlCrossRefPubMed
  42. 42.↵
    1. Rosevear HM,
    2. Lightfoot AJ,
    3. Griffith TS
    . Conatumumab, a fully human mAb against death receptor 5 for the treatment of cancer. Curr Opin Investig Drugs 2010;11:688–98.
    OpenUrlPubMed
  43. 43.↵
    1. Forero-Torres A,
    2. Shah J,
    3. Wood T,
    4. Posey J,
    5. Carlisle R,
    6. Copigneaux C,
    7. et al.
    Phase I trial of weekly tigatuzumab, an agonistic humanized monoclonal antibody targeting death receptor 5 (DR5). Cancer Biother Radiopharm 2010;25:13–9.
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. Camidge DR,
    2. Herbst RS,
    3. Gordon MS,
    4. Eckhardt SG,
    5. Kurzrock R,
    6. Durbin B,
    7. et al.
    A phase I safety and pharmacokinetic study of the death receptor 5 agonistic antibody PRO95780 in patients with advanced malignancies. Clin Cancer Res 2010;16:1256–63.
    OpenUrlAbstract/FREE Full Text
  45. 45.↵
    1. Abdulghani J,
    2. El-Deiry WS
    . TRAIL receptor signaling and therapeutics. Expert Opin Ther Targets 2010;14:1091–108.
    OpenUrlCrossRefPubMed
  46. 46.↵
    1. Plummer R,
    2. Attard G,
    3. Pacey S,
    4. Li L,
    5. Razak A,
    6. Perrett R,
    7. et al.
    Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers. Clin Cancer Res 2007;13:6187–94.
    OpenUrlAbstract/FREE Full Text
  47. 47.↵
    1. Varfolomeev E,
    2. Maecker H,
    3. Sharp D,
    4. Lawrence D,
    5. Renz M,
    6. Vucic D,
    7. et al.
    Molecular determinants of kinase pathway activation by Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand. J Biol Chem 2005;280:40599–608.
    OpenUrlAbstract/FREE Full Text
  48. 48.↵
    1. Ehrhardt H,
    2. Fulda S,
    3. Schmid I,
    4. Hiscott J,
    5. Debatin KM,
    6. Jeremias I
    . TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-kappaB. Oncogene 2003;22:3842–52.
    OpenUrlCrossRefPubMed
  49. 49.↵
    1. Soria JC,
    2. Smit E,
    3. Khayat D,
    4. Besse B,
    5. Yang X,
    6. Hsu CP,
    7. et al.
    Phase 1b study of dulanermin (recombinant human Apo2L/TRAIL) in combination with paclitaxel, carboplatin, and bevacizumab in patients with advanced non-squamous non-small-cell lung cancer. J Clin Oncol 2010;28:1527–33.
    OpenUrlAbstract/FREE Full Text
  50. 50.↵
    1. Leong S,
    2. Cohen RB,
    3. Gustafson DL,
    4. Langer CJ,
    5. Camidge DR,
    6. Padavic K,
    7. et al.
    Mapatumumab, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: results of a phase I and pharmacokinetic study. J Clin Oncol 2009;27:4413–21.
    OpenUrlAbstract/FREE Full Text
  51. 51.↵
    1. Mom CH,
    2. Verweij J,
    3. Oldenhuis CN,
    4. Gietema JA,
    5. Fox NL,
    6. Miceli R,
    7. et al.
    Mapatumumab, a fully human agonistic monoclonal antibody that targets TRAIL-R1, in combination with gemcitabine and cisplatin: a phase I study. Clin Cancer Res 2009;15:5584–90.
    OpenUrlAbstract/FREE Full Text
  52. 52.↵
    1. Yu J,
    2. Zhang L
    . PUMA, a potent killer with or without p53. Oncogene 2008;27[Suppl 1]:S71–83.
    OpenUrlCrossRefPubMed
  53. 53.↵
    1. Vogler M,
    2. Dinsdale D,
    3. Dyer MJ,
    4. Cohen GM
    . Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ 2009;16:360–7.
    OpenUrlCrossRefPubMed
  54. 54.↵
    1. Ganten TM,
    2. Haas TL,
    3. Sykora J,
    4. Stahl H,
    5. Sprick MR,
    6. Fas SC,
    7. et al.
    Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs. Cell Death Differ 2004;11[Suppl 1]:S86–96.
    OpenUrlCrossRefPubMed
  55. 55.↵
    1. Marini P,
    2. Schmid A,
    3. Jendrossek V,
    4. Faltin H,
    5. Daniel PT,
    6. Budach W,
    7. et al.
    Irradiation specifically sensitises solid tumour cell lines to TRAIL mediated apoptosis. BMC Cancer 2005;5:5.
    OpenUrlCrossRefPubMed
  56. 56.↵
    1. Guo F,
    2. Sigua C,
    3. Tao J,
    4. Bali P,
    5. George P,
    6. Li Y,
    7. et al.
    Cotreatment with histone deacetylase inhibitor LAQ824 enhances Apo-2L/tumor necrosis factor-related apoptosis inducing ligand-induced death inducing signaling complex activity and apoptosis of human acute leukemia cells. Cancer Res 2004;64:2580–9.
    OpenUrlAbstract/FREE Full Text
  57. 57.↵
    1. Shigeno M,
    2. Nakao K,
    3. Ichikawa T,
    4. Suzuki K,
    5. Kawakami A,
    6. Abiru S,
    7. et al.
    Interferon-alpha sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-kappa B inactivation. Oncogene 2003;22:1653–62.
    OpenUrlCrossRefPubMed
  58. 58.↵
    1. Herzer K,
    2. Hofmann TG,
    3. Teufel A,
    4. Schimanski CC,
    5. Moehler M,
    6. Kanzler S,
    7. et al.
    IFN-alpha-induced apoptosis in hepatocellular carcinoma involves promyelocytic leukemia protein and TRAIL independently of p53. Cancer Res 2009;69:855–62.
    OpenUrlAbstract/FREE Full Text
  59. 59.↵
    1. Stefanescu R,
    2. Bassett D,
    3. Modarresi R,
    4. Santiago F,
    5. Fakruddin M,
    6. Laurence J
    . Synergistic interactions between interferon-gamma and TRAIL modulate c-FLIP in endothelial cells, mediating their lineage-specific sensitivity to thrombotic thrombocytopenic purpura plasma-associated apoptosis. Blood 2008;112:340–9.
    OpenUrlAbstract/FREE Full Text
  60. 60.↵
    1. Brancolini C
    . Inhibitors of the Ubiquitin-Proteasome System and the cell death machinery: How many pathways are activated? Curr Mol Pharmacol 2008;1:24–37.
    OpenUrlCrossRefPubMed
  61. 61.↵
    1. Cusack JC Jr.,
    2. Liu R,
    3. Houston M,
    4. Abendroth K,
    5. Elliott PJ,
    6. Adams J,
    7. et al.
    Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res 2001;61:3535–40.
    OpenUrlAbstract/FREE Full Text
  62. 62.↵
    1. Koschny R,
    2. Ganten TM,
    3. Sykora J,
    4. Haas TL,
    5. Sprick MR,
    6. Kolb A,
    7. et al.
    TRAIL/bortezomib cotreatment is potentially hepatotoxic but induces cancer-specific apoptosis within a therapeutic window. Hepatology 2007;45:649–58.
    OpenUrlCrossRefPubMed
  63. 63.↵
    1. Voortman J,
    2. Resende TP,
    3. Abou El Hassan MA,
    4. Giaccone G,
    5. Kruyt FA
    . TRAIL therapy in non-small cell lung cancer cells: sensitization to death receptor-mediated apoptosis by proteasome inhibitor bortezomib. Mol Cancer Ther 2007;6:2103–12.
    OpenUrlAbstract/FREE Full Text
  64. 64.↵
    1. Liu X,
    2. Yue P,
    3. Chen S,
    4. Hu L,
    5. Lonial S,
    6. Khuri FR,
    7. et al.
    The proteasome inhibitor PS-341 (bortezomib) up-regulates DR5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite up-regulation of c-FLIP and survivin expression in human NSCLC cells. Cancer Res 2007;67:4981–8.
    OpenUrlAbstract/FREE Full Text
  65. 65.↵
    1. Desagher S,
    2. Osen-Sand A,
    3. Montessuit S,
    4. Magnenat E,
    5. Vilbois F,
    6. Hochmann A,
    7. et al.
    Phosphorylation of bid by casein kinases I and II regulates its cleavage by caspase 8. Mol Cell 2001;8:601–11.
    OpenUrlCrossRefPubMed
  66. 66.↵
    1. Hellwig CT,
    2. Ludwig-Galezowska AH,
    3. Concannon CG,
    4. Litchfield DW,
    5. Prehn JH,
    6. Rehm M
    . Activity of protein kinase CK2 uncouples Bid cleavage from caspase-8 activation. J Cell Sci 2010;123:1401–6.
    OpenUrlAbstract/FREE Full Text
  67. 67.↵
    1. Cursi S,
    2. Rufini A,
    3. Stagni V,
    4. Condò I,
    5. Matafora V,
    6. Bachi A,
    7. et al.
    Src kinase phosphorylates Caspase-8 on Tyr380: a novel mechanism of apoptosis suppression. EMBO J 2006;25:1895–905.
    OpenUrlCrossRefPubMed
  68. 68.↵
    1. Söderström TS,
    2. Poukkula M,
    3. Holmström TH,
    4. Heiskanen KM,
    5. Eriksson JE
    . Mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in activated T cells abrogates TRAIL-induced apoptosis upstream of the mitochondrial amplification loop and caspase-8. J Immunol 2002;169:2851–60.
    OpenUrlAbstract/FREE Full Text
  69. 69.↵
    1. Harper N,
    2. Hughes MA,
    3. Farrow SN,
    4. Cohen GM,
    5. MacFarlane M
    . Protein kinase C modulates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by targeting the apical events of death receptor signaling. J Biol Chem 2003;278:44338–47.
    OpenUrlAbstract/FREE Full Text
  70. 70.↵
    1. Tazzari PL,
    2. Tabellini G,
    3. Ricci F,
    4. Papa V,
    5. Bortul R,
    6. Chiarini F,
    7. et al.
    Synergistic proapoptotic activity of recombinant TRAIL plus the Akt inhibitor Perifosine in acute myelogenous leukemia cells. Cancer Res 2008;68:9394–403.
    OpenUrlAbstract/FREE Full Text
  71. 71.↵
    1. Fulda S,
    2. Wick W,
    3. Weller M,
    4. Debatin KM
    . Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 2002;8:808–15.
    OpenUrlPubMed
  72. 72.↵
    1. Jost PJ,
    2. Grabow S,
    3. Gray D,
    4. McKenzie MD,
    5. Nachbur U,
    6. Huang DC,
    7. et al.
    XIAP discriminates between type I and type II FAS-induced apoptosis. Nature 2009;460:1035–9.
    OpenUrlCrossRefPubMed
  73. 73.↵
    1. Vince JE,
    2. Wong WW,
    3. Khan N,
    4. Feltham R,
    5. Chau D,
    6. Ahmed AU,
    7. et al.
    IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell 2007;131:682–93.
    OpenUrlCrossRefPubMed
  74. 74.↵
    1. Varfolomeev E,
    2. Blankenship JW,
    3. Wayson SM,
    4. Fedorova AV,
    5. Kayagaki N,
    6. Garg P,
    7. et al.
    IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell 2007;131:669–81.
    OpenUrlCrossRefPubMed
  75. 75.↵
    1. Stadel D,
    2. Mohr A,
    3. Ref C,
    4. MacFarlane M,
    5. Zhou S,
    6. Humphreys R,
    7. et al.
    TRAIL-induced apoptosis is preferentially mediated via TRAIL receptor 1 in pancreatic carcinoma cells and profoundly enhanced by XIAP inhibitors. Clin Cancer Res 2010;16:5734–49.
    OpenUrlAbstract/FREE Full Text
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Molecular Cancer Therapeutics: 11 (1)
January 2012
Volume 11, Issue 1
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TRAIL Signaling and Synergy Mechanisms Used in TRAIL-Based Combination Therapies
Christian T. Hellwig and Markus Rehm
Mol Cancer Ther January 1 2012 (11) (1) 3-13; DOI: 10.1158/1535-7163.MCT-11-0434

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TRAIL Signaling and Synergy Mechanisms Used in TRAIL-Based Combination Therapies
Christian T. Hellwig and Markus Rehm
Mol Cancer Ther January 1 2012 (11) (1) 3-13; DOI: 10.1158/1535-7163.MCT-11-0434
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  • Article
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    • Introduction
    • TRAIL
    • TRAIL-Induced Apoptosis Initiation: Signaling through Death and Decoy Receptors
    • Preclinical Evidence for the Anticancer Potential of TRAIL and Its Tolerability
    • TRAIL in Clinical Trials: Monotherapies
    • TRAIL in Clinical Trials: Combination Therapies
    • Drug Classes and Their Synergy Mechanisms in TRAIL Combination Treatments
    • Conclusions
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