Skip to main content
SpringerLink
Log in

Resistance to TRAIL Pathway-Targeted Therapeutics in Cancer

  • Chapter
  • First Online:
TRAIL, Fas Ligand, TNF and TLR3 in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 12))

Abstract

As cancer therapies become more widely used, there is an increased rate of drug resistance in the population. Drug resistance has become one of the major causes of cancer treatment failure. There has been an increased use of combinational therapies in the clinic with the hopes of getting around therapeutic resistance to mono-agent chemotherapy. Unfortunately, combinational therapies present increased risks of toxicity. In developing new therapies, a key goal is to understand mechanisms of resistance and create agents that target or bypass resistance mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent and specific inducer of apoptosis in cancer cells. With little effect in normal cells, TRAIL-based therapies have become an attractive option for development. Unfortunately, a significant portion of tumor cells is relatively resistant to TRAIL, or becomes TRAIL-resistant after exposure to TRAIL-based therapies. Understanding and targeting these resistance mechanisms may help realize the therapeutic potential of the TRAIL pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hall MA, Cleveland JL (2007) Clearing the TRAIL for cancer therapy. Cancer Cell 12(1):4–6

    Article  CAS  PubMed  Google Scholar 

  2. Ashkenazi A (2008) Targeting the extrinsic apoptosis pathway in cancer. Cytokine Growth Factor Rev 19(3–4):325–331. doi:10.1016/j.cytogfr.2008.04.001

    Article  CAS  PubMed  Google Scholar 

  3. Takeda K, Stagg J, Yagita H, Okumura K, Smyth MJ (2007) Targeting death-inducing receptors in cancer therapy. Oncogene 26(25):3745–3757. doi:10.1038/sj.onc.1210374

    Article  CAS  PubMed  Google Scholar 

  4. Snell V, Clodi K, Zhao S, Goodwin R, Thomas EK, Morris SW, Kadin ME, Cabanillas F, Andreeff M, Younes A (1997) Activity of TNF-related apoptosis-inducing ligand (TRAIL) in haematological malignancies. Br J Haematol 99(3):618–624

    Article  CAS  PubMed  Google Scholar 

  5. Jeremias I, Herr I, Boehler T, Debatin KM (1998) TRAIL/Apo-2-ligand-induced apoptosis in human T cells. Eur J Immunol 28(1):143–152. doi:10.1002/(SICI)1521-4141(199801)28:01<143::AID-IMMU143>3.0.CO;2-3

    Article  CAS  PubMed  Google Scholar 

  6. Mariani SM, Krammer PH (1998) Surface expression of TRAIL/Apo-2 ligand in activated mouse T and B cells. Eur J Immunol 28(5):1492–1498. doi:10.1002/(SICI)1521-4141(199805)28:05<1492::AID-IMMU1492>3.0.CO;2-X

    Article  CAS  PubMed  Google Scholar 

  7. Monleón I, Martínez-Lorenzo MJ, Monteagudo L, Lasierra P, Taulés M, Iturralde M, Piñeiro A, Larrad L, Alava MA, Naval J, Anel A (2001) Differential secretion of Fas ligand- or APO2 ligand/TNF-related apoptosis-inducing ligand-carrying microvesicles during activation-induced death of human T cells. J Immunol 167(12):6736–6744

    Article  PubMed  Google Scholar 

  8. Kawakubo T, Okamoto K, Iwata J, Shin M, Okamoto Y, Yasukochi A, Nakayama KI, Kadowaki T, Tsukuba T, Yamamoto K (2007) Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface. Cancer Res 67(22):10869–10878. doi:10.1158/0008-5472.CAN-07-2048

    Article  CAS  PubMed  Google Scholar 

  9. Castro Alves C, Terziyska N, Grunert M, Gündisch S, Graubner U, Quintanilla-Martinez L, Jeremias I (2012) Leukemia-initiating cells of patient-derived acute lymphoblastic leukemia xenografts are sensitive toward TRAIL. Blood 119(18):4224–4227. doi:10.1182/blood-2011-08-370114

    Article  PubMed  CAS  Google Scholar 

  10. Wagner KW, Punnoose EA, Januario T, Lawrence DA, Pitti RM, Lancaster K, Lee D, von Goetz M, Yee SF, Totpal K, Huw L, Katta V, Cavet G, Hymowitz SG, Amler L, Ashkenazi A (2007) Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL. Nat Med 13(9):1070–1077. doi:10.1038/nm1627. nm1627 [pii]

  11. Lawrence D, Shahrokh Z, Marsters S, Achilles K, Shih D, Mounho B, Hillan K, Totpal K, DeForge L, Schow P, Hooley J, Sherwood S, Pai R, Leung S, Khan L, Gliniak B, Bussiere J, Smith CA, Strom SS, Kelley S, Fox JA, Thomas D, Ashkenazi A (2001) Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 7(4):383–385

    Article  CAS  PubMed  Google Scholar 

  12. Oikonomou E, Kothonidis K, Taoufik E, Probert E, Zografos G, Nasioulas G, Andera L, Pintzas A (2007) Newly established tumourigenic primary human colon cancer cell lines are sensitive to TRAIL-induced apoptosis in vitro and in vivo. Br J Cancer 97(1):73–84. doi:10.1038/sj.bjc.6603835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu GS, Burns TF, McDonald ER, Jiang W, Meng R, Krantz ID, Kao G, Gan DD, Zhou JY, Muschel R, Hamilton SR, Spinner NB, Markowitz S, Wu G, el-Deiry WS (1997) KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet 17(2):141–143. doi:10.1038/ng1097-141

  14. Carlo-Stella C, Lavazza C, Locatelli A, Viganò L, Gianni AM, Gianni L (2007) Targeting TRAIL agonistic receptors for cancer therapy. Clin Cancer Res 13(8):2313–2317. doi:10.1158/1078-0432.CCR-06-2774

    Article  CAS  PubMed  Google Scholar 

  15. Falschlehner C, Emmerich CH, Gerlach B, Walczak H (2007) TRAIL signalling: decisions between life and death. Int J Biochem Cell Biol 39(7–8):1462–1475

    Article  CAS  PubMed  Google Scholar 

  16. Corazza N, Kassahn D, Jakob S, Badmann A, Brunner T (2009) TRAIL-induced apoptosis: between tumor therapy and immunopathology. Ann N Y Acad Sci 1171:50–58. doi:10.1111/j.1749-6632.2009.04905.x

    Article  CAS  PubMed  Google Scholar 

  17. Schneider P, Thome M, Burns K, Bodmer JL, Hofmann K, Kataoka T, Holler N, Tschopp J (1997) TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity 7(6):831–836

    Article  CAS  PubMed  Google Scholar 

  18. Kelley RF, Totpal K, Lindstrom SH, Mathieu M, Billeci K, Deforge L, Pai R, Hymowitz SG, Ashkenazi A (2005) Receptor-selective mutants of apoptosis-inducing ligand 2/tumor necrosis factor-related apoptosis-inducing ligand reveal a greater contribution of death receptor (DR) 5 than DR4 to apoptosis signaling. J Biol Chem 280(3):2205–2212. doi:10.1074/jbc.M410660200

  19. Cheng J, Hylander BL, Baer MR, Chen X, Repasky EA (2006) Multiple mechanisms underlie resistance of leukemia cells to Apo2 Ligand/TRAIL. Mol Cancer Ther 5(7):1844–1853

    Article  CAS  PubMed  Google Scholar 

  20. van Geelen CM, Pennarun B, Le PT, de Vries EG, de Jong S (2011) Modulation of TRAIL resistance in colon carcinoma cells: different contributions of DR4 and DR5. BMC Cancer 11:39. doi:10.1186/1471-2407-11-39

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Yoshida T, Maeda A, Tani N, Sakai T (2001) Promoter structure and transcription initiation sites of the human death receptor 5/TRAIL-R2 gene. FEBS Lett 507(3):381–385

    Article  CAS  PubMed  Google Scholar 

  22. Oh Y, Park O, Swierczewska M, Hamilton JP, Park JS, Kim TH, Lim SM, Eom H, Jo DG, Lee CE, Kechrid R, Mastorakos P, Zhang C, Hahn SK, Jeon OC, Byun Y, Kim K, Hanes J, Lee KC, Pomper MG, Gao B, Lee S (2015) Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells. Hepatology 64(1):209–223. doi:10.1002/hep.28432

    Article  CAS  Google Scholar 

  23. Guan B, Yue P, Lotan R, Sun SY (2002) Evidence that the human death receptor 4 is regulated by activator protein 1. Oncogene 21(20):3121–3129. doi:10.1038/sj.onc.1205430

    Article  CAS  PubMed  Google Scholar 

  24. Ravi R, Bedi GC, Engstrom LW, Zeng Q, Mookerjee B, Gélinas C, Fuchs EJ, Bedi A (2001) Regulation of death receptor expression and TRAIL/Apo2L-induced apoptosis by NF-kappaB. Nat Cell Biol 3(4):409–416. doi:10.1038/35070096

    Article  CAS  PubMed  Google Scholar 

  25. Shoeb M, Ramana KV, Srivastava SK (2013) Aldose reductase inhibition enhances TRAIL-induced human colon cancer cell apoptosis through AKT/FOXO3a-dependent upregulation of death receptors. Free Radic Biol Med 63:280–290. doi:10.1016/j.freeradbiomed.2013.05.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kurita S, Mott JL, Almada LL, Bronk SF, Werneburg NW, Sun SY, Roberts LR, Fernandez-Zapico ME, Gores GJ (2010) GLI3-dependent repression of DR4 mediates hedgehog antagonism of TRAIL-induced apoptosis. Oncogene 29(34):4848–4858. doi:10.1038/onc.2010.235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM (1998) An induced proximity model for caspase-8 activation. J Biol Chem 273(5):2926–2930

    Article  CAS  PubMed  Google Scholar 

  28. Sprick MR, Rieser E, Stahl H, Grosse-Wilde A, Weigand MA, Walczak H (2002) 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 21(17):4520–4530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281(5381):1305–1308

    Article  CAS  PubMed  Google Scholar 

  30. Scott FL, Stec B, Pop C, Dobaczewska MK, Lee JJ, Monosov E, Robinson H, Salvesen GS, Schwarzenbacher R, Riedl SJ (2009) The Fas-FADD death domain complex structure unravels signalling by receptor clustering. Nature 457(7232):1019–1022. doi:10.1038/nature07606. nature07606 [pii]

  31. Wachmann K, Pop C, van Raam BJ, Drag M, Mace PD, Snipas SJ, Zmasek C, Schwarzenbacher R, Salvesen GS, Riedl SJ (2010) Activation and specificity of human caspase-10. Biochemistry 49(38):8307–8315. doi:10.1021/bi100968m

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94(4):491–501

    Article  CAS  PubMed  Google Scholar 

  33. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94(4):481–490

    Article  CAS  PubMed  Google Scholar 

  34. Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC, Lynch DH (1999) Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 5(2):157–163

    Article  CAS  PubMed  Google Scholar 

  35. Zhang L, Zhang X, Barrisford GW, Olumi AF (2007) Lexatumumab (TRAIL-receptor 2 mAb) induces expression of DR5 and promotes apoptosis in primary and metastatic renal cell carcinoma in a mouse orthotopic model. Cancer Lett 251(1):146–157

    Article  CAS  PubMed  Google Scholar 

  36. Holoch PA, Griffith TS (2009) TNF-related apoptosis-inducing ligand (TRAIL): a new path to anti-cancer therapies. Eur J Pharmacol 625(1–3):63–72. doi:10.1016/j.ejphar.2009.06.066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nguyen DX, Bos PD, Massagué J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9(4):274–284. doi:10.1038/nrc2622

    Article  CAS  PubMed  Google Scholar 

  38. Eccles SA, Welch DR (2007) Metastasis: recent discoveries and novel treatment strategies. Lancet 369(9574):1742–1757. doi:10.1016/S0140-6736(07)60781-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Simpson CD, Anyiwe K, Schimmer AD (2008) Anoikis resistance and tumor metastasis. Cancer Lett 272(2):177–185. doi:10.1016/j.canlet.2008.05.029

    Article  CAS  PubMed  Google Scholar 

  40. Zhou XD, Yu JP, Liu J, Luo HS, Chen HX, Yu HG (2004) Overexpression of cellular FLICE-inhibitory protein (FLIP) in gastric adenocarcinoma. Clin Sci 106(4):397–405

    Article  CAS  PubMed  Google Scholar 

  41. Jönsson G, Paulie S, Grandien A (2003) High level of cFLIP correlates with resistance to death receptor-induced apoptosis in bladder carcinoma cells. Anticancer Res 23(2B):1213–1218

    PubMed  Google Scholar 

  42. Weigelt B, Peterse JL, van’t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5(8):591–602. doi:10.1038/nrc1670

    Article  CAS  PubMed  Google Scholar 

  43. Grosse-Wilde A, Voloshanenko O, Bailey SL, Longton GM, Schaefer U, Csernok AI, Schütz G, Greiner EF, Kemp CJ, Walczak H (2008) TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development. J Clin Invest 118(1):100–110. doi:10.1172/JCI33061

    Article  CAS  PubMed  Google Scholar 

  44. Laguinge LM, Samara RN, Wang W, El-Deiry WS, Corner G, Augenlicht L, Mishra L, Jessup JM (2008) DR5 receptor mediates anoikis in human colorectal carcinoma cell lines. Cancer Res 68(3):909–917. doi:10.1158/0008-5472.CAN-06-1806

    Article  CAS  PubMed  Google Scholar 

  45. Elrod HA, Fan S, Muller S, Chen GZ, Pan L, Tighiouart M, Shin DM, Khuri FR, Sun SY (2010) Analysis of death receptor 5 and caspase-8 expression in primary and metastatic head and neck squamous cell carcinoma and their prognostic impact. PLoS One 5(8):e12178. doi:10.1371/journal.pone.0012178

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Malin D, Chen F, Schiller C, Koblinski J, Cryns VL (2011) Enhanced metastasis suppression by targeting TRAIL receptor 2 in a murine model of triple-negative breast cancer. Clin Cancer Res 17(15):5005–5015. doi:10.1158/1078-0432.CCR-11-0099

    Article  CAS  PubMed  Google Scholar 

  47. Trauzold A, Siegmund D, Schniewind B, Sipos B, Egberts J, Zorenkov D, Emme D, Röder C, Kalthoff H, Wajant H (2006) TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma. Oncogene 25(56):7434–7439. doi:10.1038/sj.onc.1209719

    Article  CAS  PubMed  Google Scholar 

  48. Hoogwater FJ, Nijkamp MW, Smakman N, Steller EJ, Emmink BL, Westendorp BF, Raats DA, Sprick MR, Schaefer U, Van Houdt WJ, De Bruijn MT, Schackmann RC, Derksen PW, Medema JP, Walczak H, Borel Rinkes IH, Kranenburg O (2010) Oncogenic K-Ras turns death receptors into metastasis-promoting receptors in human and mouse colorectal cancer cells. Gastroenterology 138(7):2357–2367. doi:10.1053/j.gastro.2010.02.046

    Article  CAS  PubMed  Google Scholar 

  49. Sun SY (2011) Understanding the role of the death receptor 5/FADD/caspase-8 death signaling in cancer metastasis. Mol Cell Pharmacol 3(1):31–34

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z, Schwall RH (1999) Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 104(2):155–162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jo M, Kim TH, Seol DW, Esplen JE, Dorko K, Billiar TR, Strom SC (2000) Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med 6(5):564–567

    Article  CAS  PubMed  Google Scholar 

  52. Nitsch R, Bechmann I, Deisz RA, Haas D, Lehmann TN, Wendling U, Zipp F (2000) Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL). Lancet 356(9232):827–828. doi:10.1016/S0140-6736(00)02659-3

    Article  CAS  PubMed  Google Scholar 

  53. Srivastava RK (2001) TRAIL/Apo-2L: mechanisms and clinical applications in cancer. Neoplasia 3(6):535–546. doi:10.1038/sj/neo/7900203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kayagaki N, Yamaguchi N, Nakayama M, Kawasaki A, Akiba H, Okumura K, Yagita H (1999) Involvement of TNF-related apoptosis-inducing ligand in human CD4+ T cell-mediated cytotoxicity. J Immunol 162(5):2639–2647

    CAS  PubMed  Google Scholar 

  55. Hayakawa Y, Screpanti V, Yagita H, Grandien A, Ljunggren HG, Smyth MJ, Chambers BJ (2004) NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy. J Immunol 172(1):123–129

    Article  CAS  PubMed  Google Scholar 

  56. Janssen EM, Droin NM, Lemmens EE, Pinkoski MJ, Bensinger SJ, Ehst BD, Griffith TS, Green DR, Schoenberger SP (2005) CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 434(7029):88–93

    Article  CAS  PubMed  Google Scholar 

  57. Kim TH, Youn YS, Jiang HH, Lee S, Chen X, Lee KC (2011) PEGylated TNF-related apoptosis-inducing ligand (TRAIL) analogues: pharmacokinetics and antitumor effects. Bioconjug Chem 22(8):1631–1637. doi:10.1021/bc200187k

    Article  CAS  PubMed  Google Scholar 

  58. Kim SM, Lim JY, Park SI, Jeong CH, Oh JH, Jeong M, Oh W, Park SH, Sung YC, Jeun SS (2008) Gene therapy using TRAIL-secreting human umbilical cord blood-derived mesenchymal stem cells against intracranial glioma. Cancer Res 68(23):9614–9623. doi:10.1158/0008-5472.CAN-08-0451

    Article  CAS  PubMed  Google Scholar 

  59. Sasportas LS, Kasmieh R, Wakimoto H, Hingtgen S, van de Water JA, Mohapatra G, Figueiredo JL, Martuza RL, Weissleder R, Shah K (2009) Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy. Proc Natl Acad Sci U S A 106(12):4822–4827. doi:10.1073/pnas.0806647106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Läubli H, Borsig L (2010) Selectins promote tumor metastasis. Semin Cancer Biol 20(3):169–177. doi:10.1016/j.semcancer.2010.04.005

    Article  PubMed  CAS  Google Scholar 

  61. Seifert O, Pollak N, Nusser A, Steiniger F, Rüger R, Pfizenmaier K, Kontermann RE (2014) Immuno-LipoTRAIL: targeted delivery of TRAIL-functionalized liposomal nanoparticles. Bioconjug Chem 25(5):879–887. doi:10.1021/bc400517j

    Article  CAS  PubMed  Google Scholar 

  62. Mitchell MJ, Wayne E, Rana K, Schaffer CB, King MR (2014) TRAIL-coated leukocytes that kill cancer cells in the circulation. Proc Natl Acad Sci U S A 111(3):930–935. doi:10.1073/pnas.1316312111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. De Miguel D, Gallego-Lleyda A, Anel A, Martinez-Lostao L (2015) Liposome-bound TRAIL induces superior DR5 clustering and enhanced DISC recruitment in histiocytic lymphoma U937 cells. Leuk Res 39(6):657–666. doi:10.1016/j.leukres.2015.03.019

    Article  PubMed  CAS  Google Scholar 

  64. De Miguel D, Gallego-Lleyda A, Galan-Malo P, Rodriguez-Vigil C, Marzo I, Anel A, Martinez-Lostao L (2015) Immunotherapy with liposome-bound TRAIL overcomes partial protection to soluble TRAIL-induced apoptosis offered by down-regulation of Bim in leukemic cells. Clin Transl Oncol 17(8):657–667. doi:10.1007/s12094-015-1295-x

    Article  PubMed  CAS  Google Scholar 

  65. Buchsbaum DJ, Zhou T, Grizzle WE, Oliver PG, Hammond CJ, Zhang S, Carpenter M, LoBuglio AF (2003) Antitumor efficacy of TRA-8 anti-DR5 monoclonal antibody alone or in combination with chemotherapy and/or radiation therapy in a human breast cancer model. Clin Cancer Res 9(10 Pt 1):3731–3741

    CAS  PubMed  Google Scholar 

  66. Ichikawa K, Liu W, Zhao L, Wang Z, Liu D, Ohtsuka T, Zhang H, Mountz JD, Koopman WJ, Kimberly RP, Zhou T (2001) Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat Med 7(8):954–960

    Article  CAS  PubMed  Google Scholar 

  67. Soria JC, Márk Z, Zatloukal P, Szima B, Albert I, Juhász E, Pujol JL, Kozielski J, Baker N, Smethurst D, Hei YJ, Ashkenazi A, Stern H, Amler L, Pan Y, Blackhall F (2011) Randomized phase II study of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non-small-cell lung cancer. J Clin Oncol 29(33):4442–4451. doi:10.1200/JCO.2011.37.2623

    Article  CAS  PubMed  Google Scholar 

  68. Thorburn A, Behbakht K, Ford H (2008) TRAIL receptor-targeted therapeutics: resistance mechanisms and strategies to avoid them. Drug Resist Updat 11(1–2):17–24. doi:10.1016/j.drup.2008.02.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. von Pawel J, Harvey JH, Spigel DR, Dediu M, Reck M, Cebotaru CL, Humphreys RC, Gribbin MJ, Fox NL, Camidge DR (2014) Phase II trial of mapatumumab, a fully human agonist monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer. Clin Lung Cancer 15(3):188–196 e182. doi:10.1016/j.cllc.2013.12.005

  70. Tolcher AW, Mita M, Meropol NJ, von Mehren M, Patnaik A, Padavic K, Hill M, Mays T, McCoy T, Fox NL, Halpern W, Corey A, Cohen RB (2007) 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 25(11):1390–1395

    Article  CAS  PubMed  Google Scholar 

  71. Hotte SJ, Hirte HW, Chen EX, Siu LL, Le LH, Corey A, Iacobucci A, MacLean M, Lo L, Fox NL, Oza AM (2008) A phase 1 study of mapatumumab (fully human monoclonal antibody to TRAIL-R1) in patients with advanced solid malignancies. Clin Cancer Res 14(11):3450–3455. doi:10.1158/1078-0432.CCR-07-1416. 14/11/3450 [pii]

  72. Trarbach T, Moehler M, Heinemann V, Köhne CH, Przyborek M, Schulz C, Sneller V, Gallant G, Kanzler S (2010) 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 102(3):506–512. doi:10.1038/sj.bjc.6605507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Horak P, Pils D, Haller G, Pribill I, Roessler M, Tomek S, Horvat R, Zeillinger R, Zielinski C, Krainer M (2005) Contribution of epigenetic silencing of tumor necrosis factor-related apoptosis inducing ligand receptor 1 (DR4) to TRAIL resistance and ovarian cancer. Mol Cancer Res 3(6):335–343

    Article  CAS  PubMed  Google Scholar 

  74. MacFarlane M, Kohlhaas SL, Sutcliffe MJ, Dyer MJ, Cohen GM (2005) TRAIL receptor-selective mutants signal to apoptosis via TRAIL-R1 in primary lymphoid malignancies. Cancer Res 65(24):11265–11270. doi:10.1158/0008-5472.CAN-05-2801

    Article  CAS  PubMed  Google Scholar 

  75. Milutinovic S, Kashyap AK, Yanagi T, Wimer C, Zhou S, O’Neil R, Kurtzman AL, Faynboym A, Xu L, Hannum CH, Diaz PW, Matsuzawa S, Horowitz M, Horowitz L, Bhatt RR, Reed JC (2016) Dual agonist surrobody simultaneously activates death receptors DR4 and DR5 to induce cancer cell death. Mol Cancer Ther 15(1):114–124. doi:10.1158/1535-7163.MCT-15-0400

    Article  CAS  PubMed  Google Scholar 

  76. Allen JE, Krigsfeld G, Mayes PA, Patel L, Dicker DT, Patel AS, Dolloff NG, Messaris E, Scata KA, Wang W, Zhou JY, Wu GS, El-Deiry WS (2013) Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Sci Transl Med 5(171):171ra117. doi:10.1126/scitranslmed.3004828

    Article  CAS  Google Scholar 

  77. Kline CL, Van den Heuvel AP, Allen JE, Prabhu VV, Dicker DT, El-Deiry WS (2016) ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases. Sci Signal 9(415):ra18. doi:10.1126/scisignal.aac4374

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Prabhu VV, Allen JE, Dicker DT, El-Deiry WS (2015) Small-molecule ONC201/TIC10 targets chemotherapy-resistant colorectal cancer stem-like cells in an Akt/Foxo3a/TRAIL-dependent manner. Cancer Res 75(7):1423–1432. doi:10.1158/0008-5472.CAN-13-3451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Di Pietro R, Zauli G (2004) Emerging non-apoptotic functions of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L. J Cell Physiol 201(3):331–340. doi:10.1002/jcp.20099

    Article  PubMed  CAS  Google Scholar 

  80. Jin Z, McDonald ER, Dicker DT, El-Deiry WS (2004) Deficient tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor transport to the cell surface in human colon cancer cells selected for resistance to TRAIL-induced apoptosis. J Biol Chem 279(34):35829–35839. doi:10.1074/jbc.M405538200

    Article  CAS  PubMed  Google Scholar 

  81. Zhang Y, Zhang B (2008) TRAIL resistance of breast cancer cells is associated with constitutive endocytosis of death receptors 4 and 5. Mol Cancer Res 6(12):1861–1871. doi:10.1158/1541-7786.MCR-08-0313

    Article  CAS  PubMed  Google Scholar 

  82. Lee SH, Shin MS, Kim HS, Lee HK, Park WS, Kim SY, Lee JH, Han SY, Park JY, Oh RR, Kang CS, Kim KM, Jang JJ, Nam SW, Lee JY, Yoo NJ (2001) Somatic mutations of TRAIL-receptor 1 and TRAIL-receptor 2 genes in non-Hodgkin’s lymphoma. Oncogene 20(3):399–403

    Article  CAS  PubMed  Google Scholar 

  83. Ozören N, Fisher MJ, Kim K, Liu CX, Genin A, Shifman Y, Dicker DT, Spinner NB, Lisitsyn NA, El-Deiry WS (2000) Homozygous deletion of the death receptor DR4 gene in a nasopharyngeal cancer cell line is associated with TRAIL resistance. Int J Oncol 16(5):917–925

    PubMed  Google Scholar 

  84. Emi M, Fujiwara Y, Nakajima T, Tsuchiya E, Tsuda H, Hirohashi S, Maeda Y, Tsuruta K, Miyaki M, Nakamura Y (1992) Frequent loss of heterozygosity for loci on chromosome 8p in hepatocellular carcinoma, colorectal cancer, and lung cancer. Cancer Res 52(19):5368–5372

    CAS  PubMed  Google Scholar 

  85. Wistuba II, Behrens C, Virmani AK, Milchgrub S, Syed S, Lam S, Mackay B, Minna JD, Gazdar AF (1999) Allelic losses at chromosome 8p21-23 are early and frequent events in the pathogenesis of lung cancer. Cancer Res 59(8):1973–1979

    CAS  PubMed  Google Scholar 

  86. Hopkins-Donaldson S, Ziegler A, Kurtz S, Bigosch C, Kandioler D, Ludwig C, Zangemeister-Wittke U, Stahel R (2003) Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation. Cell Death Differ 10(3):356–364

    Article  CAS  PubMed  Google Scholar 

  87. Horak P, Pils D, Kaider A, Pinter A, Elandt K, Sax C, Zielinski CC, Horvat R, Zeillinger R, Reinthaller A, Krainer M (2005) Perturbation of the tumor necrosis factor--related apoptosis-inducing ligand cascade in ovarian cancer: overexpression of FLIPL and deregulation of the functional receptors DR4 and DR5. Clin Cancer Res 11(24 Pt 1):8585–8591. doi:10.1158/1078-0432.CCR-05-1276

    Article  CAS  PubMed  Google Scholar 

  88. Elias A, Siegelin MD, Steinmüller A, von Deimling A, Lass U, Korn B, Mueller W (2009) Epigenetic silencing of death receptor 4 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in gliomas. Clin Cancer Res 15(17):5457–5465. doi:10.1158/1078-0432.CCR-09-1125

    Article  CAS  PubMed  Google Scholar 

  89. Dechant C, Schauenberg P, Antoni CE, Kraetsch HG, Kalden JR, Manger B (2004) [Longterm outcome of TNF blockade in adult-onset Still’s disease]. Dtsch Med Wochenschr 129(23):1308–1312. doi:10.1055/s-2004-826865

  90. Fulda S (2009) Caspase-8 in cancer biology and therapy. Cancer Lett 281(2):128–133. doi:10.1016/j.canlet.2008.11.023

    Article  CAS  PubMed  Google Scholar 

  91. Fulda S (2008) Modulation of TRAIL-induced apoptosis by HDAC inhibitors. Curr Cancer Drug Targets 8(2):132–140

    Article  CAS  PubMed  Google Scholar 

  92. Bin L, Thorburn J, Thomas LR, Clark PE, Humphreys R, Thorburn A (2007) Tumor-derived mutations in the TRAIL receptor DR5 inhibit TRAIL signaling through the DR4 receptor by competing for ligand binding. J Biol Chem 282(38):28189–28194. doi:10.1074/jbc.M704210200. M704210200 [pii]

  93. Du W, Uslar L, Sevala S, Shah K (2014) Targeting c-met receptor overcomes TRAIL-resistance in brain tumors. PLoS One 9(4):e95490. doi:10.1371/journal.pone.0095490

    Article  PubMed  PubMed Central  Google Scholar 

  94. Abounader R, Reznik T, Colantuoni C, Martinez-Murillo F, Rosen EM, Laterra J (2004) Regulation of c-Met-dependent gene expression by PTEN. Oncogene 23(57):9173–9182. doi:10.1038/sj.onc.1208146

    CAS  PubMed  Google Scholar 

  95. Kojima Y, Nakayama M, Nishina T, Nakano H, Koyanagi M, Takeda K, Okumura K, Yagita H (2011) Importin β≤1 protein-mediated nuclear localization of death receptor 5 (DR5) limits DR5/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced cell death of human tumor cells. J Biol Chem 286(50):43383–43393. doi:10.1074/jbc.M111.309377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Di X, Zhang G, Zhang Y, Takeda K, Rivera Rosado LA, Zhang B (2013) Accumulation of autophagosomes in breast cancer cells induces TRAIL resistance through downregulation of surface expression of death receptors 4 and 5. Oncotarget 4(9):1349–1364. doi:10.18632/oncotarget.1174

    Article  PubMed  PubMed Central  Google Scholar 

  97. Austin CD, Lawrence DA, Peden AA, Varfolomeev EE, Totpal K, De Mazière AM, Klumperman J, Arnott D, Pham V, Scheller RH, Ashkenazi A (2006) Death-receptor activation halts clathrin-dependent endocytosis. Proc Natl Acad Sci U S A 103(27):10283–10288. doi:10.1073/pnas.0604044103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Singh TR, Shankar S, Srivastava RK (2005) HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma. Oncogene 24(29):4609–4623. doi:10.1038/sj.onc.1208585

    Article  CAS  PubMed  Google Scholar 

  99. Srivastava RK, Kurzrock R, Shankar S (2010) MS-275 sensitizes TRAIL-resistant breast cancer cells, inhibits angiogenesis and metastasis, and reverses epithelial-mesenchymal transition in vivo. Mol Cancer Ther 9(12):3254–3266. doi:10.1158/1535-7163.MCT-10-0582

    Article  CAS  PubMed  Google Scholar 

  100. Venza I, Visalli M, Oteri R, Teti D, Venza M (2014) Class I-specific histone deacetylase inhibitor MS-275 overrides TRAIL-resistance in melanoma cells by downregulating c-FLIP. Int Immunopharmacol 21(2):439–446. doi:10.1016/j.intimp.2014.05.024

    Article  CAS  PubMed  Google Scholar 

  101. Eramo A, Pallini R, Lotti F, Sette G, Patti M, Bartucci M, Ricci-Vitiani L, Signore M, Stassi G, Larocca LM, Crinò L, Peschle C, De Maria R (2005) Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction. Cancer Res 65(24):11469–11477. doi:10.1158/0008-5472.CAN-05-1724

    Article  CAS  PubMed  Google Scholar 

  102. Degli-Esposti MA, Dougall WC, Smolak PJ, Waugh JY, Smith CA, Goodwin RG (1997) The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 7(6):813–820

    Article  CAS  PubMed  Google Scholar 

  103. Held J, Schulze-Osthoff K (2001) Potential and caveats of TRAIL in cancer therapy. Drug Resist Updat 4(4):243–252. doi:10.1054/drup.2001.0208

    Article  CAS  PubMed  Google Scholar 

  104. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM (1997) An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 277(5327):815–818

    Article  CAS  PubMed  Google Scholar 

  105. Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, DiPrinzio R, Dodds RA, James IE, Rosenberg M, Lee JC, Young PR (1998) Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 273(23):14363–14367

    Article  CAS  PubMed  Google Scholar 

  106. Kurokawa H, Nishio K, Fukumoto H, Tomonari A, Suzuki T, Saijo N (1999) Alteration of caspase-3 (CPP32/Yama/apopain) in wild-type MCF-7, breast cancer cells. Oncol Rep 6(1):33–37

    CAS  PubMed  Google Scholar 

  107. Li C, Egloff AM, Sen M, Grandis JR, Johnson DE (2014) Caspase-8 mutations in head and neck cancer confer resistance to death receptor-mediated apoptosis and enhance migration, invasion, and tumor growth. Mol Oncol 8(7):1220–1230. doi:10.1016/j.molonc.2014.03.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, Fakhry C, Xie TX, Zhang J, Wang J, Zhang N, El-Naggar AK, Jasser SA, Weinstein JN, Treviño L, Drummond JA, Muzny DM, Wu Y, Wood LD, Hruban RH, Westra WH, Koch WM, Califano JA, Gibbs RA, Sidransky D, Vogelstein B, Velculescu VE, Papadopoulos N, Wheeler DA, Kinzler KW, Myers JN (2011) Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333(6046):1154–1157. doi:10.1126/science.1206923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kim HS, Lee JW, Soung YH, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ, Jeong SW, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH (2003) Inactivating mutations of caspase-8 gene in colorectal carcinomas. Gastroenterology 125(3):708–715

    Article  CAS  PubMed  Google Scholar 

  110. Tschopp J, Irmler M, Thome M (1998) Inhibition of fas death signals by FLIPs. Curr Opin Immunol 10(5):552–558

    Article  CAS  PubMed  Google Scholar 

  111. Krueger A, Schmitz I, Baumann S, Krammer PH, Kirchhoff S (2001) Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. J Biol Chem 276(23):20633–20640

    Article  CAS  PubMed  Google Scholar 

  112. Bagnoli M, Canevari S, Mezzanzanica D (2010) Cellular FLICE-inhibitory protein (c-FLIP) signalling: a key regulator of receptor-mediated apoptosis in physiologic context and in cancer. Int J Biochem Cell Biol 42(2):210–213. doi:10.1016/j.biocel.2009.11.015. S1357-2725(09)00345-8 [pii]

  113. Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schröter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388(6638):190–195. doi:10.1038/40657

    Article  CAS  PubMed  Google Scholar 

  114. McCourt C, Maxwell P, Mazzucchelli R, Montironi R, Scarpelli M, Salto-Tellez M, O’Sullivan JM, Longley DB, Waugh DJ (2012) Elevation of c-FLIP in castrate-resistant prostate cancer antagonizes therapeutic response to androgen receptor-targeted therapy. Clin Cancer Res 18(14):3822–3833. doi:10.1158/1078-0432.CCR-11-3277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wilson TR, McLaughlin KM, McEwan M, Sakai H, Rogers KM, Redmond KM, Johnston PG, Longley DB (2007) c-FLIP: a key regulator of colorectal cancer cell death. Cancer Res 67(12):5754–5762. doi:10.1158/0008-5472.CAN-06-3585. 67/12/5754 [pii]

  116. Chen F, Guo J, Zhang Y, Zhao Y, Zhou N, Liu S, Liu Y, Zheng D (2009) Knockdown of c-FLIP(L) enhanced AD5-10 anti-death receptor 5 monoclonal antibody-induced apoptosis in human lung cancer cells. Cancer Sci 100(5):940–947. doi:10.1111/j.1349-7006.2009.01119.x

    Article  CAS  PubMed  Google Scholar 

  117. Kim SH, Ricci MS, El-Deiry WS (2008) Mcl-1: a gateway to TRAIL sensitization. Cancer Res 68(7):2062–2064. doi:10.1158/0008-5472.CAN-07-6278

    Article  CAS  PubMed  Google Scholar 

  118. Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed JC (1998) IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 17(8):2215–2223. doi:10.1093/emboj/17.8.2215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Giagkousiklidis S, Vellanki SH, Debatin KM, Fulda S (2007) Sensitization of pancreatic carcinoma cells for gamma-irradiation-induced apoptosis by XIAP inhibition. Oncogene 26(49):7006–7016. doi:10.1038/sj.onc.1210502

    Article  CAS  PubMed  Google Scholar 

  120. Vogler M, Dürr K, Jovanovic M, Debatin KM, Fulda S (2007) Regulation of TRAIL-induced apoptosis by XIAP in pancreatic carcinoma cells. Oncogene 26(2):248–257. doi:10.1038/sj.onc.1209776

    Article  CAS  PubMed  Google Scholar 

  121. Vogler M, Walczak H, Stadel D, Haas TL, Genze F, Jovanovic M, Gschwend JE, Simmet T, Debatin KM, Fulda S (2008) Targeting XIAP bypasses Bcl-2-mediated resistance to TRAIL and cooperates with TRAIL to suppress pancreatic cancer growth in vitro and in vivo. Cancer Res 68(19):7956–7965. doi:10.1158/0008-5472.CAN-08-1296

    Article  CAS  PubMed  Google Scholar 

  122. Mohr A, Albarenque SM, Deedigan L, Yu R, Reidy M, Fulda S, Zwacka RM (2010) Targeting of XIAP combined with systemic mesenchymal stem cell-mediated delivery of sTRAIL ligand inhibits metastatic growth of pancreatic carcinoma cells. Stem Cells 28(11):2109–2120. doi:10.1002/stem.533

    Article  CAS  PubMed  Google Scholar 

  123. Nakahara T, Kita A, Yamanaka K, Mori M, Amino N, Takeuchi M, Tominaga F, Hatakeyama S, Kinoyama I, Matsuhisa A, Kudoh M, Sasamata M (2007) YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res 67(17):8014–8021. doi:10.1158/0008-5472.CAN-07-1343

    Article  CAS  PubMed  Google Scholar 

  124. Premkumar DR, Jane EP, Foster KA, Pollack IF (2013) Survivin inhibitor YM-155 sensitizes tumor necrosis factor- related apoptosis-inducing ligand-resistant glioma cells to apoptosis through Mcl-1 downregulation and by engaging the mitochondrial death pathway. J Pharmacol Exp Ther 346(2):201–210. doi:10.1124/jpet.113.204743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Allensworth JL, Sauer SJ, Lyerly HK, Morse MA, Devi GR (2013) Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism. Breast Cancer Res Treat 137(2):359–371. doi:10.1007/s10549-012-2352-6

    Article  CAS  PubMed  Google Scholar 

  126. Fakler M, Loeder S, Vogler M, Schneider K, Jeremias I, Debatin KM, Fulda S (2009) Small molecule XIAP inhibitors cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells and overcome Bcl-2-mediated resistance. Blood 113(8):1710–1722. doi:10.1182/blood-2007-09-114314

    Article  CAS  PubMed  Google Scholar 

  127. Kim SY, Park SE, Shim SM, Park S, Kim KK, Jeong SY, Choi EK, Hwang JJ, Jin DH, Chung CD, Kim I (2015) Bay 61-3606 sensitizes TRAIL-induced apoptosis by downregulating Mcl-1 in breast cancer cells. PLoS One 10(12):e0146073. doi:10.1371/journal.pone.0146073

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Hetschko H, Voss V, Horn S, Seifert V, Prehn JH, Kogel D (2008) Pharmacological inhibition of Bcl-2 family members reactivates TRAIL-induced apoptosis in malignant glioma. J Neuro-Oncol 86(3):265–272. doi:10.1007/s11060-007-9472-6

    Article  CAS  Google Scholar 

  129. Kucharczak J, Simmons MJ, Fan Y, Gélinas C (2003) To be, or not to be: NF-kappaB is the answer--role of Rel/NF-kappaB in the regulation of apoptosis. Oncogene 22(56):8961–8982. doi:10.1038/sj.onc.1207230

    Article  CAS  PubMed  Google Scholar 

  130. Ammann JU, Haag C, Kasperczyk H, Debatin KM, Fulda S (2009) Sensitization of neuroblastoma cells for TRAIL-induced apoptosis by NF-kappaB inhibition. Int J Cancer 124(6):1301–1311. doi:10.1002/ijc.24068

    Article  CAS  PubMed  Google Scholar 

  131. Thomas RP, Farrow BJ, Kim S, May MJ, Hellmich MR, Evers BM (2002) Selective targeting of the nuclear factor-kappaB pathway enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated pancreatic cancer cell death. Surgery 132(2):127–134

    Article  PubMed  Google Scholar 

  132. Ravi R, Bedi A (2002) Requirement of BAX for TRAIL/Apo2L-induced apoptosis of colorectal cancers: synergism with sulindac-mediated inhibition of Bcl-x(L). Cancer Res 62(6):1583–1587

    CAS  PubMed  Google Scholar 

  133. Crowder RN, Dicker DT, El-Deiry WS (2016) The deubiquitinase inhibitor PR-619 sensitizes normal human fibroblasts to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cell death. J Biol Chem 291(11):5960–5970. doi:10.1074/jbc.M115.713545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Leverkus M, Neumann M, Mengling T, Rauch CT, Bröcker EB, Krammer PH, Walczak H (2000) Regulation of tumor necrosis factor-related apoptosis-inducing ligand sensitivity in primary and transformed human keratinocytes. Cancer Res 60(3):553–559

    CAS  PubMed  Google Scholar 

  135. Mirandola P, Ponti C, Gobbi G, Sponzilli I, Vaccarezza M, Cocco L, Zauli G, Secchiero P, Manzoli FA, Vitale M (2004) Activated human NK and CD8+ T cells express both TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors but are resistant to TRAIL-mediated cytotoxicity. Blood 104(8):2418–2424

    Article  CAS  PubMed  Google Scholar 

  136. van Dijk M, Halpin-McCormick A, Sessler T, Samali A, Szegezdi E (2013) Resistance to TRAIL in non-transformed cells is due to multiple redundant pathways. Cell Death Dis 4:e702. doi:10.1038/cddis.2013.214

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Song JJ, An JY, Kwon YT, Lee YJ (2007) Evidence for two modes of development of acquired tumor necrosis factor-related apoptosis-inducing ligand resistance. Involvement of Bcl-xL. J Biol Chem 282(1):319–328. doi:10.1074/jbc.M608065200

    Article  CAS  PubMed  Google Scholar 

  138. Song JH, Bellail A, Tse MC, Yong VW, Hao C (2006) Human astrocytes are resistant to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. J Neurosci 26(12):3299–3308

    Article  CAS  PubMed  Google Scholar 

  139. Yoshida T, Zhang Y, Rivera Rosado LA, Zhang B (2009) Repeated treatment with subtoxic doses of TRAIL induces resistance to apoptosis through its death receptors in MDA-MB-231 breast cancer cells. Mol Cancer Res 7(11):1835–1844. doi:10.1158/1541-7786.MCR-09-0244

    Article  CAS  PubMed  Google Scholar 

  140. Lane D, Côté M, Grondin R, Couture MC, Piché A (2006) Acquired resistance to TRAIL-induced apoptosis in human ovarian cancer cells is conferred by increased turnover of mature caspase-3. Mol Cancer Ther 5(3):509–521. doi:10.1158/1535-7163.MCT-05-0362

    Article  CAS  PubMed  Google Scholar 

  141. Zhang XD, Wu JJ, Gillespie S, Borrow J, Hersey P (2006) Human melanoma cells selected for resistance to apoptosis by prolonged exposure to tumor necrosis factor-related apoptosis-inducing ligand are more vulnerable to necrotic cell death induced by cisplatin. Clin Cancer Res 12(4):1355–1364. doi:10.1158/1078-0432.CCR-05-2084

    Article  CAS  PubMed  Google Scholar 

  142. Herbst RS, Eckhardt SG, Kurzrock R, Ebbinghaus S, O’Dwyer PJ, Gordon MS, Novotny W, Goldwasser MA, Tohnya TM, Lum BL, Ashkenazi A, Jubb AM, Mendelson DS (2010) Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer. J Clin Oncol 28(17):2839–2846. doi:10.1200/JCO.2009.25.1991. JCO.2009.25.1991 [pii]

  143. Camidge DR (2008) Apomab: an agonist monoclonal antibody directed against death receptor 5/TRAIL-receptor 2 for use in the treatment of solid tumors. Expert Opin Biol Ther 8(8):1167–1176. doi:10.1517/14712598.8.8.1167

    Article  CAS  PubMed  Google Scholar 

  144. Wakelee HA, Patnaik A, Sikic BI, Mita M, Fox NL, Miceli R, Ullrich SJ, Fisher GA, Tolcher AW (2010) Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors. Ann Oncol 21 (2):376–381. doi:10.1093/annonc/mdp292. mdp292 [pii]

  145. Kindler HL, Richards DA, Garbo LE, Garon EB, Stephenson JJ, Rocha-Lima CM, Safran H, Chan D, Kocs DM, Galimi F, McGreivy J, Bray SL, Hei Y, Feigal EG, Loh E, Fuchs CS (2012) A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Ann Oncol 23(11):2834–2842. doi:10.1093/annonc/mds142

    Article  CAS  PubMed  Google Scholar 

  146. Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413

    Article  CAS  PubMed  Google Scholar 

  147. Ozawa F, Friess H, Kleeff J, Xu ZW, Zimmermann A, Sheikh MS, Büchler MW (2001) Effects and expression of TRAIL and its apoptosis-promoting receptors in human pancreatic cancer. Cancer Lett 163(1):71–81

    Article  CAS  PubMed  Google Scholar 

  148. Rajeshkumar NV, Rasheed ZA, García-García E, López-Ríos F, Fujiwara K, Matsui WH, Hidalgo M (2010) A combination of DR5 agonistic monoclonal antibody with gemcitabine targets pancreatic cancer stem cells and results in long-term disease control in human pancreatic cancer model. Mol Cancer Ther 9(9):2582–2592. doi:10.1158/1535-7163.MCT-10-0370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Kaplan-Lefko PJ, Graves JD, Zoog SJ, Pan Y, Wall J, Branstetter DG, Moriguchi J, Coxon A, Huard JN, Xu R, Peach ML, Juan G, Kaufman S, Chen Q, Bianchi A, Kordich JJ, Ma M, Foltz IN, Gliniak BC (2010) Conatumumab, a fully human agonist antibody to death receptor 5, induces apoptosis via caspase activation in multiple tumor types. Cancer Biol Ther 9(8):618–631

    Article  CAS  PubMed  Google Scholar 

  150. Forero-Torres A, Infante JR, Waterhouse D, Wong L, Vickers S, Arrowsmith E, He AR, Hart L, Trent D, Wade J, Jin X, Wang Q, Austin T, Rosen M, Beckman R, von Roemeling R, Greenberg J, Saleh M (2013) Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer. Cancer Med 2(6):925–932. doi:10.1002/cam4.137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Gliniak B, Le T (1999) Tumor necrosis factor-related apoptosis-inducing ligand’s antitumor activity in vivo is enhanced by the chemotherapeutic agent CPT-11. Cancer Res 59(24):6153–6158

    CAS  PubMed  Google Scholar 

  152. Liu Y, Meyer C, Xu C, Weng H, Hellerbrand C, ten Dijke P, Dooley S (2013) Animal models of chronic liver diseases. Am J Physiol Gastrointest Liver Physiol 304(5):G449–G468. doi:10.1152/ajpgi.00199.2012

    Article  CAS  PubMed  Google Scholar 

  153. Takimoto R, El-Deiry WS (2000) Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site. Oncogene 19(14):1735–1743. doi:10.1038/sj.onc.1203489

    Article  CAS  PubMed  Google Scholar 

  154. Keane MM, Ettenberg SA, Nau MM, Russell EK, Lipkowitz S (1999) Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. Cancer Res 59(3):734–741

    CAS  PubMed  Google Scholar 

  155. Nimmanapalli R, Perkins CL, Orlando M, O’Bryan E, Nguyen D, Bhalla KN (2001) Pretreatment with paclitaxel enhances apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels. Cancer Res 61(2):759–763

    CAS  PubMed  Google Scholar 

  156. Mizutani Y, Yoshida O, Miki T, Bonavida B (1999) Synergistic cytotoxicity and apoptosis by Apo-2 ligand and adriamycin against bladder cancer cells. Clin Cancer Res 5(9):2605–2612

    CAS  PubMed  Google Scholar 

  157. Bonvini P, Zorzi E, Basso G, Rosolen A (2007) Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma. Leukemia 21(4):838–842. doi:10.1038/sj.leu.2404528

    CAS  PubMed  Google Scholar 

  158. Sayers TJ, Brooks AD, Koh CY, Ma W, Seki N, Raziuddin A, Blazar BR, Zhang X, Elliott PJ, Murphy WJ (2003) The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. Blood 102(1):303–310

    Article  CAS  PubMed  Google Scholar 

  159. Seki N, Toh U, Sayers TJ, Fujii T, Miyagi M, Akagi Y, Kusukawa J, Kage M, Shirouzu K, Yamana H (2010) Bortezomib sensitizes human esophageal squamous cell carcinoma cells to TRAIL-mediated apoptosis via activation of both extrinsic and intrinsic apoptosis pathways. Mol Cancer Ther 9(6):1842–1851. doi:10.1158/1535-7163.MCT-09-0918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Brooks AD, Ramirez T, Toh U, Onksen J, Elliott PJ, Murphy WJ, Sayers TJ (2005) The proteasome inhibitor bortezomib (Velcade) sensitizes some human tumor cells to Apo2L/TRAIL-mediated apoptosis. Ann N Y Acad Sci 1059:160–167. doi:10.1196/annals.1339.042

    Article  CAS  PubMed  Google Scholar 

  161. Llobet D, Eritja N, Yeramian A, Pallares J, Sorolla A, Domingo M, Santacana M, Gonzalez-Tallada FJ, Matias-Guiu X, Dolcet X (2010) The multikinase inhibitor Sorafenib induces apoptosis and sensitises endometrial cancer cells to TRAIL by different mechanisms. Eur J Cancer 46(4):836–850. doi:10.1016/j.ejca.2009.12.025

    Article  CAS  PubMed  Google Scholar 

  162. Kriegl L, Jung A, Engel J, Jackstadt R, Gerbes AL, Gallmeier E, Reiche JA, Hermeking H, Rizzani A, Bruns CJ, Kolligs FT, Kirchner T, Göke B, De Toni EN (2010) Expression, cellular distribution, and prognostic relevance of TRAIL receptors in hepatocellular carcinoma. Clin Cancer Res 16(22):5529–5538. doi:10.1158/1078-0432.CCR-09-3403

    Article  CAS  PubMed  Google Scholar 

  163. Ciuleanu T, Bazin I, Lungulescu D, Miron L, Bondarenko I, Deptala A, Rodriguez-Torres M, Giantonio B, Fox NL, Wissel P, Egger J, Ding M, Kalyani RN, Humphreys R, Gribbin M, Sun W (2016) A randomized, double-blind, placebo-controlled phase II study to assess the efficacy and safety of mapatumumab with sorafenib in patients with advanced hepatocellular carcinoma. Ann Oncol 27(4):680–687. doi:10.1093/annonc/mdw004

    Article  CAS  PubMed  Google Scholar 

  164. Fulda S, Debatin KM (2005) Resveratrol-mediated sensitisation to TRAIL-induced apoptosis depends on death receptor and mitochondrial signalling. Eur J Cancer 41(5):786–798. doi:10.1016/j.ejca.2004.12.020

    Article  CAS  PubMed  Google Scholar 

  165. Schneider P, Holler N, Bodmer JL, Hahne M, Frei K, Fontana A, Tschopp J (1998) Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity. J Exp Med 187(8):1205–1213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Plummer R, Attard G, Pacey S, Li L, Razak A, Perrett R, Barrett M, Judson I, Kaye S, Fox NL, Halpern W, Corey A, Calvert H, de Bono J (2007) Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers. Clin Cancer Res 13(20):6187–6194. doi:10.1158/1078-0432.CCR-07-0950. 13/20/6187 [pii]

  167. Loebinger MR, Eddaoudi A, Davies D, Janes SM (2009) Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res 69(10):4134–4142. doi:10.1158/0008-5472.CAN-08-4698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Perlstein B, Finniss SA, Miller C, Okhrimenko H, Kazimirsky G, Cazacu S, Lee HK, Lemke N, Brodie S, Umansky F, Rempel SA, Rosenblum M, Mikklesen T, Margel S, Brodie C (2013) TRAIL conjugated to nanoparticles exhibits increased anti-tumor activities in glioma cells and glioma stem cells in vitro and in vivo. Neuro-Oncology 15(1):29–40. doi:10.1093/neuonc/nos248

    Article  CAS  PubMed  Google Scholar 

  169. Jiang CC, Chen LH, Gillespie S, Kiejda KA, Mhaidat N, Wang YF, Thorne R, Zhang XD, Hersey P (2007) 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 67(12):5880–5888. doi:10.1158/0008-5472.CAN-07-0213

    Article  CAS  PubMed  Google Scholar 

  170. He L, Jang JH, Choi HG, Lee SM, Nan MH, Jeong SJ, Dong Z, Kwon YT, Lee KS, Lee KW, Chung JK, Ahn JS, Kim BY (2013) Oligomycin a enhances apoptotic effect of TRAIL through CHOP-mediated death receptor 5 expression. Mol Carcinog 52(2):85–93. doi:10.1002/mc.21831

    Article  PubMed  CAS  Google Scholar 

  171. Jane EP, Premkumar DR, Pollack IF (2011) Bortezomib sensitizes malignant human glioma cells to TRAIL, mediated by inhibition of the NF-{kappa}B signaling pathway. Mol Cancer Ther 10(1):198–208. doi:10.1158/1535-7163.MCT-10-0725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Li X, Huang T, Jiang G, Gong W, Qian H, Zou C (2013) Proteasome inhibitor MG132 enhances TRAIL-induced apoptosis and inhibits invasion of human osteosarcoma OS732 cells. Biochem Biophys Res Commun 439(2):179–186. doi:10.1016/j.bbrc.2013.08.066

    Article  CAS  PubMed  Google Scholar 

  173. Nakata S, Yoshida T, Horinaka M, Shiraishi T, Wakada M, Sakai T (2004) Histone deacetylase inhibitors upregulate death receptor 5/TRAIL-R2 and sensitize apoptosis induced by TRAIL/APO2-L in human malignant tumor cells. Oncogene 23(37):6261–6271

    Article  CAS  PubMed  Google Scholar 

  174. Newsom-Davis T, Prieske S, Walczak H (2009) Is TRAIL the holy grail of cancer therapy? Apoptosis 14(4):607–623. doi:10.1007/s10495-009-0321-2

    Article  CAS  PubMed  Google Scholar 

  175. Abdulghani J, Allen JE, Dicker DT, Liu YY, Goldenberg D, Smith CD, Humphreys R, El-Deiry WS (2013) Sorafenib sensitizes solid tumors to Apo2L/TRAIL and Apo2L/TRAIL receptor agonist antibodies by the Jak2-Stat3-Mcl1 axis. PLoS One 8(9):e75414. doi:10.1371/journal.pone.0075414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Hamed HA, Yamaguchi Y, Fisher PB, Grant S, Dent P (2013) Sorafenib and HDAC inhibitors synergize with TRAIL to kill tumor cells. J Cell Physiol 228(10):1996–2005. doi:10.1002/jcp.24362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Miyashita K, Shiraki K, Fuke H, Inoue T, Yamanaka Y, Yamaguchi Y, Yamamoto N, Ito K, Sugimoto K, Nakano T (2006) The cyclin-dependent kinase inhibitor flavopiridol sensitizes human hepatocellular carcinoma cells to TRAIL-induced apoptosis. Int J Mol Med 18(2):249–256

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology/Oncology and Molecular Therapeutics Program, Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA

    Jessica Wagner, Christina Leah Kline & Wafik El-Deiry

Authors
  1. Jessica Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christina Leah Kline
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wafik El-Deiry
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wafik El-Deiry .

Editor information

Editors and Affiliations

  1. INSERM, LNC UMR 1231, Dijon, France

    Olivier Micheau

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Wagner, J., Kline, C.L., El-Deiry, W. (2017). Resistance to TRAIL Pathway-Targeted Therapeutics in Cancer. In: Micheau, O. (eds) TRAIL, Fas Ligand, TNF and TLR3 in Cancer. Resistance to Targeted Anti-Cancer Therapeutics, vol 12. Springer, Cham. https://doi.org/10.1007/978-3-319-56805-8_1

Download citation

Publish with us

Policies and ethics

Search

Navigation