TRAIL and Other TRAIL Receptor Agonists as Novel Cancer Therapeutics

  • Christina Falschlehner
  • Tom M. Ganten
  • Ronald Koschny
  • Uta Schaefer
  • Henning Walczak
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 647)


Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo2L, is a member of the TNF superfamily (TNFSF) of cytokines. TRAIL gained much attention during the past decade due to the demonstration of its therapeutic potential as a tumor-specific apoptosis inducer. TRAIL was identified as a protein with high homology to other members of the TNF cytokine family, especially to the ligand of Fas/Apo-1 (CD95), CD95L (FasL/APO-1L). TRAIL has been shown to induce apoptosis selectively in many tumor cell lines without affecting normal cells and tissues, making TRAIL itself as well as agonists of the two human receptors of TRAIL which can submit an apoptotic signal, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), promising novel biotherapeutics for cancer therapy. An increasing number of publications now shows that TRAIL resistance in primary human tumor cells will have to be overcome and that sensitization to TRAIL-induced apoptosis will be required in many cases. Therefore, it will also be instrumental to develop suitable diagnostic tests to identify patients who will benefit from TRAIL-based novel anticancer therapeutics and those who will not. Interestingly, the first clinical results even in monotherapy with TRAIL as well as various agonistic TRAIL receptor-specific antibodies have shown encouraging results. This chapter provides a compact overview on the biochemistry of the TRAIL/TRAIL-R system, the physiological role of TRAIL and its receptors and the results of clinical trials with TRAIL and various TRAIL-R agonistic antibodies.


Biliary Tract Cancer Advanced Solid Tumor Trail Receptor Tumor Necrosis Factor Superfamily Trail Resistance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Pan G, O’Rourke K, Chinnaiyan AM et al. The receptor for the cytotoxic ligand TRAIL. Science 1997; 276:111–113.PubMedCrossRefGoogle Scholar
  2. 2.
    Screaton GR, Mongkolsapaya J, Xu XN et al. TRICK2, a new alternatively spliced receptor that transduces the cytotoxic signal from TRAIL. Curr Biol 1997; 7:693–696.PubMedCrossRefGoogle Scholar
  3. 3.
    Sheridan JP, Marsters SA, Pitti RM et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997; 277:818–821.PubMedCrossRefGoogle Scholar
  4. 4.
    Walczak H, Degli-Esposti MA, Johnson RS et al. TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J 1997; 16:5386–5397.PubMedCrossRefGoogle Scholar
  5. 5.
    Daniel PT, Wieder T, et al. The kiss of death: promises and failures of death receptors and ligands in cancer therapy. Leukemia 2001; 15(7):1022–32.PubMedCrossRefGoogle Scholar
  6. 6.
    Kimberley FC, Screaton GR. Following a TRAIL: update on a ligand and its five receptors. Cell Res 2004; 14(5):359–372.PubMedCrossRefGoogle Scholar
  7. 7.
    Walczak H, Sprick MR. Biochemistry and function of the DISC. Trends Biochem Sci 2001; 26(7):452–3.PubMedCrossRefGoogle Scholar
  8. 8.
    Chen M, Orozco A et al. Activation of initiator caspases through a stable dimeric intermediate. J Biol Chem 2002; 277(52):50761–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Sprick MR, Rieser E et al. Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8. EMBO J 2002; 21(17):4520–30.PubMedCrossRefGoogle Scholar
  10. 10.
    Xiao C, Yang BF et al. Tumor necrosis factor-related apoptosis-inducing ligand-induced death-inducing signaling complex and its modulation by c-FLIP and PED/PEA-15 in glioma cells. J Biol Chem 2002; 277(28):25020–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Creagh EM, Martin SJ. Caspases: cellular demolition experts. Biochem Soc Trans 2001; 29(Pt 6):696–702.PubMedCrossRefGoogle Scholar
  12. 12.
    Baliga, B, Kumar S. Apaf-1/cytochrome c apoptosome: an essential initiator of caspase activation or just a sideshow? Cell Death Differ 2003; 10(1):16–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Strasser A, The role of BH3-only proteins in the immune system. Nature reviews 2005; 5:189–200.PubMedCrossRefGoogle Scholar
  14. 14.
    Wei MC, Lindsten T et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 2000; 14(16):2060–71.PubMedGoogle Scholar
  15. 15.
    Villunger A, Michalak EM et al. p53-and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 2003; 302(5647):1036–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Purhalakath H, O’Reilly LA et al. ER stress trigger apoptosis by activating BH3-only protein Bim. Cell 2007; 129(7):1337–49.CrossRefGoogle Scholar
  17. 17.
    Verhagen AM, Ekert PG et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 2000; 102(1):43–53.PubMedCrossRefGoogle Scholar
  18. 18.
    Suzuki Y, Imai Y et al. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell 2001a; 8(3):613–21.PubMedCrossRefGoogle Scholar
  19. 19.
    Riedl SJ, Salvesen GS. The apoptosome: signalling platform of cell death. Nat Rev Mol Cell Biol 2007; 8(5):405–13.PubMedCrossRefGoogle Scholar
  20. 20.
    Eckelman BP, Salvesen GS et al. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep 2006; 7(10):988–94.PubMedCrossRefGoogle Scholar
  21. 21.
    Suzuki Y, Nakabayashi Y et al. X-linked inhibitor of apoptosis protein (XIAP) inhibits caspase-3 and-7 in distinct modes. J Biol Chem 2001b; 276(29):27058–63.PubMedCrossRefGoogle Scholar
  22. 22.
    Cretney E, Takeda K, Yagita H et al. Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 2002; 168:1356–1361.PubMedGoogle Scholar
  23. 23.
    Diehl GE, Yue HH, Hsieh K et al. TRAIL-R as a negative regulator of innate immune cell responses. Immunity 2004; 21:877–889.PubMedCrossRefGoogle Scholar
  24. 24.
    Finnberg N, Gruber JJ, Fei P et al. DR5 knockout mice are compromised in radiation-induced apoptosis. Mol Cell Biol 2005; 25:2000–2013.PubMedCrossRefGoogle Scholar
  25. 25.
    Sedger LM, Glaccum MB, Schuh JC et al. Characterization of the in vivo function of TNF-alpha-related apoptosis-inducing ligand, TRAIL/Apo2L, using TRAIL/Apo2L gene-deficient mice. Eur J Immunol 2002; 32:2246–2254.PubMedCrossRefGoogle Scholar
  26. 26.
    Yue HH, Diehl GE, Winoto A. Loss of TRAIL-R does not affect thymic or intestinal tumor development in p53 and adenomatous polyposis coli mutant mice. Cell Death Differ 2005; 12:94–97.PubMedCrossRefGoogle Scholar
  27. 27.
    Zerafa N, Westwood JA, Cretney E et al. Cutting edge: TRAIL deficiency accelerates hematological malignancies. J Immunol 2005; 175:5586–5590.PubMedGoogle Scholar
  28. 28.
    Ehrlich S, Infante-Duarte C et al. Regulation of soluble and surface-bound TRAIL in human T-cells, B-cells and monocytes. Cytokine 2003; 24(6):244–53.PubMedCrossRefGoogle Scholar
  29. 29.
    Halaas O, Vik R et al. Lipopolysaccharide induces expression of APO2 ligand/TRAIL in human monocytes and macrophages. Scand J Immunol 2000; 51(3):244–50.PubMedCrossRefGoogle Scholar
  30. 30.
    Takeda K, Smyth MJ et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in NK cell-mediated and IFN-gamma-dependent suppression of subcutaneous tumor growth. Cell Immunol 2001; 214(2):194–200.PubMedCrossRefGoogle Scholar
  31. 31.
    Cretney E, Uldrich AP, Berzins SP et al. Normal thymocyte negative selection in TRAIL-deficient mice. J Exp Med 2003; 198:491–496.PubMedCrossRefGoogle Scholar
  32. 32.
    Lamhamedi-Cherradi SE, Zheng S, Tisch RM et al. Critical roles of tumor necrosis factor-related apoptosis-inducing ligand in type 1 diabetes. Diabetes 2003a; 52:2274–2278.PubMedCrossRefGoogle Scholar
  33. 33.
    Lamhamedi-Cherradi SE, Zheng SJ, Maguschak KA et al. Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL-/-mice. Nat Immunol 2003b; 4:255–260.PubMedCrossRefGoogle Scholar
  34. 34.
    Wang SH, Cao Z et al. Death ligand tumor necrosis factor-related apoptosis-inducing ligand inhibits experimental autoimmune thyroiditis. Endocrinology 2005; 146(11):4721–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Cretney E, McQualter JL, Kayagaki N et al. TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L suppresses experimental autoimmune encephalomyelitis in mice. Immunol Cell Biol 2005a; 83:511–519.PubMedCrossRefGoogle Scholar
  36. 36.
    Aktas O, Smorodchenko A et al. Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL. Neuron 2005; 46(3):421–32.PubMedCrossRefGoogle Scholar
  37. 37.
    Janssen EM, Droin NM et al. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 2005; 434(7029):88–93.PubMedCrossRefGoogle Scholar
  38. 38.
    Hamilton SE, Wolkers MC et al. The generation of protective memory-like CD8+ T-cells during homeostatic proliferation requires CD4+ T-cells. Nat Immunol 2006; 7(5):475–81.PubMedCrossRefGoogle Scholar
  39. 39.
    Griffith TS, Kazama H et al. Apoptotic cells induce tolerance by generating helpless CD8+ T-cells that produce TRAIL. J Immunol 2007; 178(5):2679–87.PubMedGoogle Scholar
  40. 40.
    Gazitt Y, TRAIL is a potent inducer of apoptosis in myeloma cells derived from multiple myeloma patients and is not cytotoxic to hematopoietic stem cells. Leukemia 1999; 13:1817–1824.PubMedCrossRefGoogle Scholar
  41. 41.
    Mitsiades CS, Treon SP, Mitsiades N et al. TRAIL/Apo 2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood 2001; 98:795–804.PubMedCrossRefGoogle Scholar
  42. 42.
    Clodi K, Wimmer D, Li Y et al. Expression of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors and sensitivity to TRAIL-induced apoptosis in primary B-cell acute lymphoblastic leukaemia cells. British journal of haematology 2000; 111:580–586.PubMedCrossRefGoogle Scholar
  43. 43.
    MacFarlane M, Harper N, Snowden RT et al. Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia. Oncogene 2002; 21:6809–6818.PubMedCrossRefGoogle Scholar
  44. 44.
    Snell V, Clodi K, Zhao S et al. Activity of TNF-related apoptosis-inducing ligand (TRAIL) in haematological malignancies. British journal of haematology 1997; 99:618–624.PubMedCrossRefGoogle Scholar
  45. 45.
    Panner A, James CD, Berger MS et al. mTOR controls FLIPS translation and TRAIL sensitivity in glioblastoma multiforme cells. Mol Cell Biol 2005; 25:8809–8823.PubMedCrossRefGoogle Scholar
  46. 46.
    Koschny R, Holland H et al. Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Clin Cancer Res 2007b; 13(11):3403–12.PubMedCrossRefGoogle Scholar
  47. 47.
    Clayer M, Bouralexis S, Evdokiou A et al. Enhanced apoptosis of soft tissue sarcoma cells with chemotherapy: A potential new approach using TRAIL. J Orthop Surg (Hong Kong) 2001; 9:19–22.Google Scholar
  48. 48.
    Hayakawa Y, Screpanti V, Yagita H et al. NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy. J Immunol 2004; 172:123–129.PubMedGoogle Scholar
  49. 49.
    Secchiero P, Zerbinati C, Rimondi E et al. TRAIL promotes the survival, migration and proliferation of vascular smooth muscle cells. Cell Mol Life Sci 2004; 61:1965–1974.PubMedCrossRefGoogle Scholar
  50. 50.
    Ishimura N, Isomoto H, Bronk SF et al. Trail induces cell migration and invasion in apoptosis-resistant cholangiocarcinoma cells. Am J Physiol Gastrointest Liver Physiol 2006; 290:G129–136.PubMedCrossRefGoogle Scholar
  51. 51.
    Trauzold A, Siegmund D, Schniewind B et al. TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma. Oncogene 2006; 25:7434–7439.PubMedCrossRefGoogle Scholar
  52. 52.
    Ashkenazi A, Pai RC et al. Safety and antitumor activity of recombinant soluble Apo 2 ligand. J Clin Invest 1999;104(2):155–62.PubMedCrossRefGoogle Scholar
  53. 53.
    Walczak H, Miller RE, Ariail K et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 1999; 5:157–163.PubMedCrossRefGoogle Scholar
  54. 54.
    Camidge D, Herbst RS, Gordon M et al. Mendelson; Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol. 25, No. 18S (Supplement) 2007:3582.Google Scholar
  55. 55.
    Jing Li, Betty Tang, Cheng Jean et al. Novartis Inst. for BioMed. Research, Inc., Cambridge, MA, Genomics Institute of the Novartis Research Foundation, San Diego, CA; Poster; AACR Meeting 2007, Los Angeles, CA.Google Scholar
  56. 56.
    Nebbioso A, Clarke N, Voltz E et al. Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat Med 2005; 11:77–84.PubMedCrossRefGoogle Scholar
  57. 57.
    Inoue S, MacFarlane M, Harper N et al. Histone deacetylase inhibitors potentiate TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in lymphoid malignancies. Cell Death Differ 2004; 11Suppl 2: S193–206.CrossRefGoogle Scholar
  58. 58.
    MacFarlane M, Kohlhaas SL, Sutcliffe MJ et al. TRAIL receptor-selective mutants signal to apoptosis via TRAIL-R1 in primary lymphoid malignancies. Cancer Res 2005; 65:11265–11270.PubMedCrossRefGoogle Scholar
  59. 59.
    Olsson A, Diaz T, Aguilar-Santelises M et al. Sensitization to TRAIL-induced apoptosis and modulation of FLICE-inhibitory protein in B chronic lymphocytic leukemia by actinomycin D. Leukemia 2001; 15:1868–1877.PubMedGoogle Scholar
  60. 60.
    Mitsiades N, Mitsiades CS, Poulaki V et al. Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications. Blood 2002; 99:4079–4086.PubMedCrossRefGoogle Scholar
  61. 61.
    Di Pietro R, Secchiero P, Rana R et al. Ionizing radiation sensitizes erythroleukemia cells but not normal erythroblasts to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)—mediated cytotoxicity by selective up-regulation of TRAIL-R1. Blood 2001; 97:2596–2603.PubMedCrossRefGoogle Scholar
  62. 62.
    Naka T, Sugamura K, Hylander BL et al. Effects of tumor necrosis factor-related apoptosis-inducing ligand alone and in combination with chemotherapeutic agents on patients’ colon tumors grown in SCID mice. Cancer Res 2002; 62:5800–5806.PubMedGoogle Scholar
  63. 63.
    Hylander BL, Pitoniak R, Penetrante RB et al. The anti-tumor effect of Apo2L/TRAIL on patient pancreatic adenocarcinomas grown as xenografts in SCID mice. J Transl Med, 2005; 3:22.PubMedCrossRefGoogle Scholar
  64. 64.
    Ganten TM, Koschny R, Haas TL et al. Proteasome inhibition sensitizes hepatocellular carcinoma cells, but not human hepatocytes, to TRAIL. Hepatology, 2005; 42:588–597.PubMedCrossRefGoogle Scholar
  65. 65.
    Ganten TM, Koschny R, Sykora J et al. Preclinical differentiation between apparently safe and potentially hepatotoxic applications of TRAIL either alone or in combination with chemotherapeutic drugs. Clin Cancer Res 2006; 12:2640–2646.PubMedCrossRefGoogle Scholar
  66. 66.
    Koschny R, Ganten TM et al. TRAIL/bortezomib cotreatment is potentially hepatotoxic but induces cancer-specific apoptosis within a therapeutic window. Hepatology 2007a; 45(3):649–58.PubMedCrossRefGoogle Scholar
  67. 67.
    Pathil A, Armeanu S, Venturelli S et al. HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL. Hepatology 2006; 43:425–434.PubMedCrossRefGoogle Scholar
  68. 68.
    Leverkus M, Sprick MR, Wachter T et al. Proteasome inhibition results in TRAIL sensitization of primary keratinocytes by removing the resistance-mediating block of effector caspase maturation. Mol Cell Biol 2003; 23:777–790.PubMedCrossRefGoogle Scholar
  69. 69.
    Nakata S, Yoshida T, Horinaka M et al. Histone deacetylase inhibitors upregulate death receptor 5/TRAIL-R2 and sensitize apoptosis induced by TRAIL/APO2-L in human malignant tumor cells. Oncogene 2004; 23:6261–6271.PubMedCrossRefGoogle Scholar
  70. 70.
    Atkins GJ, Bouralexis S, Evdokiou A et al. Human osteoblasts are resistant to Apo2L/TRAIL-mediated apoptosis. Bone 2002; 31:448–456.PubMedCrossRefGoogle Scholar
  71. 71.
    Van Valen F, Fulda S, Schafer KL et al. Selective and nonselective toxicity of TRAIL/Apo2L combined with chemotherapy in human bone tumour cells vs. normal human cells. International journal of cancer 2003; 107:929–940.CrossRefGoogle Scholar
  72. 72.
    Wu XX, Kakehi Y, Mizutani Y et al. Doxorubicin enhances TRAIL-induced apoptosis in prostate cancer. Int J Oncol 2002; 20:949–954.PubMedGoogle Scholar
  73. 73.
    Cretney E, Uldrich AP, Berzins SP et al. Are we really on the right TRAIL?, Immunol Res 2005b; 31:161–164.PubMedCrossRefGoogle Scholar
  74. 74.
    Koschny R, Walczak H, Ganten TM. The promise of TRAIL-potential and risks of a novel anti-cancer therapy. J Mol Med 2007.Google Scholar
  75. 75.
    Jin X, Wu XX, et al. Enhancement of death receptor 4 mediated apoptosis and cytotoxicity in renal cell carcinoma cells by subtoxic concentrations of doxorubicin. J Urol 2007; 177(5):1894–1899.PubMedCrossRefGoogle Scholar
  76. 76.
    Jiang CC, Chen LH, et al. Tunicamycin sensitizes human melanoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by up-regulation of TRAIL-R2 via the unfolded protein response. Cancer Res 2007; 67(12):5880–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Volkmann X, Fischer U, et al. Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver. Hepatology. 2007. (published online in advance of print)Google Scholar
  78. 78.
    Meurette O, Fontaine A, et al. Cytotoxicity of TRAIL/anticancer drug combinations in human normal cells. Ann N Y Acad Sci 2006; 1090:209–16.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Christina Falschlehner
    • 1
  • Tom M. Ganten
    • 2
  • Ronald Koschny
    • 2
  • Uta Schaefer
    • 3
  • Henning Walczak
    • 1
  1. 1.Department of Immunology Division of MedicineImperial College LondonLondonUK
  2. 2.Internal MedicineUniversity of HeidelbergHeidelbergGermany
  3. 3.Division of Apoptosis RegulationGerman Cancer Research CenterHeidelbergGermany

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