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TRAIL-R2-specific antibodies and recombinant TRAIL can synergise to kill cancer cells

Oncogene volume 34, pages 2138–2144 (2015)Cite this article

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Abstract

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells while sparing normal tissues. Despite promising preclinical results, few patients responded to treatment with recombinant TRAIL (Apo2L/Dulanermin) or TRAIL-R2-specific antibodies, such as conatumumab (AMG655). It is unknown whether this was due to intrinsic TRAIL resistance within primary human cancers or insufficient agonistic activity of the TRAIL-receptor (TRAIL-R)-targeting drugs. Fcγ receptors (FcγR)-mediated crosslinking increases the cancer-cell-killing activity of TRAIL-R2-specific antibodies in vivo. We tested this phenomenon using FcγR-expressing immune cells from patients with ovarian cancer. However, even in the presence of high numbers of FcγR-expressing immune cells, as found in ovarian cancer ascites, AMG655-induced apoptosis was not enabled to any significant degree, indicating that this concept may not translate into clinical use. On the basis of these results, we next set out to determine whether AMG655 possibly interferes with apoptosis induction by endogenous TRAIL, which could be expressed by immune cells. To do so, we tested how AMG655 affected apoptosis induction by recombinant TRAIL. This, however, resulted in the surprising discovery of a striking synergy between AMG655 and non-tagged TRAIL (Apo2L/TRAIL) in killing cancer cells. This combination was as effective in killing cancer cells as highly active recombinant isoleucine-zipper-tagged TRAIL (iz-TRAIL). The increased killing efficiency was due to enhanced formation of the TRAIL death-inducing signalling complex, enabled by concomitant binding of Apo2L/TRAIL and AMG655 to TRAIL-R2. The synergy of AMG655 with Apo2L/TRAIL extended to primary ovarian cancer cells and was further enhanced by combination with the proteasome inhibitor bortezomib or a second mitochondrial-derived activator of caspases (SMAC) mimetic. Importantly, primary human hepatocytes were not killed by the AMG655-Apo2L/TRAIL combination, also not when further combined with bortezomib or a SMAC mimetic. We therefore propose that clinical-grade non-tagged recombinant forms of TRAIL, such as dulanermin, could be combined with antibodies such as AMG655 to introduce a highly active TRAIL-R2-agonistic therapy into the cancer clinic.

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References

  1. Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 1999; 5: 157–163.

    Article  CAS  Google Scholar 

  2. Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999; 104: 155–162.

    Article  CAS  Google Scholar 

  3. Lawrence D, Shahrokh Z, Marsters S, Achilles K, Shih D, Mounho B et al. Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 2001; 7: 383–385.

    Article  CAS  Google Scholar 

  4. Ganten TM, Koschny R, Sykora J, Schulze-Bergkamen H, Buchler P, Haas TL 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.

    Article  CAS  Google Scholar 

  5. Herbst RS, Eckhardt SG, Kurzrock R, Ebbinghaus S, O'Dwyer PJ, Gordon MS 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: 2839–2846.

    Article  CAS  Google Scholar 

  6. Newsom-Davis T, Prieske S, Walczak H . Is TRAIL the holy grail of cancer therapy? Apoptosis 2009; 14: 607–623.

    Article  CAS  Google Scholar 

  7. Kaplan-Lefko PJ, Graves JD, Zoog SJ, Pan Y, Wall J, Branstetter DG et al. Conatumumab, a fully human agonist antibody to death receptor 5, induces apoptosis via caspase activation in multiple tumor types. Cancer Biol Ther 2010; 9: 618–631.

    Article  CAS  Google Scholar 

  8. Soria JC, Mark Z, Zatloukal P, Szima B, Albert I, Juhasz E et al. Randomized phase II study of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non-small-cell lung cancer. J Clin Oncol 2011; 29: 4442–4451.

    Article  CAS  Google Scholar 

  9. Kindler HL, Richards DA, Garbo LE, Garon EB, Stephenson JJ Jr, Rocha-Lima CM et al. 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 2012; 23: 2834–2842.

    Article  CAS  Google Scholar 

  10. Paz-Ares L, Balint B, de Boer RH, van Meerbeeck JP, Wierzbicki R, De Souza P et al. A randomized phase 2 study of paclitaxel and carboplatin with or without conatumumab for first-line treatment of advanced non-small-cell lung cancer. J Thoracic Oncol 2013; 8: 329–337.

    Article  CAS  Google Scholar 

  11. Plummer R, Attard G, Pacey S, Li L, Razak A, Perrett R et al. Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers. Clin Cancer Res 2007; 13: 6187–6194.

    Article  CAS  Google Scholar 

  12. Wilson NS, Yang B, Yang A, Loeser S, Marsters S, Lawrence D et al. An Fcgamma receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells. Cancer Cell 2011; 19: 101–113.

    Article  CAS  Google Scholar 

  13. Haynes NM, Hawkins ED, Li M, McLaughlin NM, Hammerling GJ, Schwendener R et al. CD11c+ dendritic cells and B cells contribute to the tumoricidal activity of anti-DR5 antibody therapy in established tumors. J Immunol 2010; 185: 532–541.

    Article  CAS  Google Scholar 

  14. Leinster DA, Kulbe H, Everitt G, Thompson R, Perretti M, Gavins FN et al. The peritoneal tumour microenvironment of high-grade serous ovarian cancer. J Pathol 2012; 227: 136–145.

    Article  CAS  Google Scholar 

  15. Saulle E, Petronelli A, Pasquini L, Petrucci E, Mariani G, Biffoni M et al. Proteasome inhibitors sensitize ovarian cancer cells to TRAIL induced apoptosis. Apoptosis 2007; 12: 635–655.

    Article  CAS  Google Scholar 

  16. Petrucci E, Pasquini L, Bernabei M, Saulle E, Biffoni M, Accarpio F et al. A small molecule SMAC mimic LBW242 potentiates TRAIL- and anticancer drug-mediated cell death of ovarian cancer cells. PLoS ONE 2012; 7: e35073.

    Article  CAS  Google Scholar 

  17. Petrucci E, Pasquini L, Bernabei M, Saulle E, Biffoni M, Accarpio F et al. A small molecule SMAC mimic LBW242 potentiates TRAIL- and anticancer drug-mediated cell death of ovarian cancer cells. PLoS ONE 2012; 7: e35073.

    Article  CAS  Google Scholar 

  18. Taieb J, Chaput N, Menard C, Apetoh L, Ullrich E, Bonmort M et al. A novel dendritic cell subset involved in tumor immunosurveillance. Nat Med 2006; 12: 214–219.

    Article  CAS  Google Scholar 

  19. Herbst RS, Kurzrock R, Hong DS, Valdivieso M, Hsu CP, Goyal L et al. A first-in-human study of conatumumab in adult patients with advanced solid tumors. Clin Cancer Res 2010; 16: 5883–5891.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Goncharenko-Khaider N, Lane D, Matte I, Rancourt C, Piche A . The inhibition of Bid expression by Akt leads to resistance to TRAIL-induced apoptosis in ovarian cancer cells. Oncogene Engl 2010; 29: 5523–5536.

    Article  CAS  Google Scholar 

  22. Gillissen B, Richter A, Overkamp T, Essmann F, Hemmati PG, Preissner R et al. Targeted therapy of the XIAP/proteasome pathway overcomes TRAIL-resistance in carcinoma by switching apoptosis signaling to a Bax/Bak-independent 'type I' mode. Cell Death Dis 2013; 4: e643.

    Article  CAS  Google Scholar 

  23. Fulda S, Wick W, Weller M, 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: 808–815.

    Article  CAS  Google Scholar 

  24. Vogler M, Walczak H, Stadel D, Haas TL, Genze F, Jovanovic M et al. 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 2008; 68: 7956–7965.

    Article  CAS  Google Scholar 

  25. Ganten TM, Koschny R, Haas TL, Sykora J, Li-Weber M, Herzer K et al. Proteasome inhibition sensitizes hepatocellular carcinoma cells, but not human hepatocytes, to TRAIL. Hepatology (Baltimore, Md) 2005; 42: 588–597.

    Article  CAS  Google Scholar 

  26. Koschny R, Ganten TM, Sykora J, Haas TL, Sprick MR, Kolb A et al. TRAIL/bortezomib cotreatment is potentially hepatotoxic but induces cancer-specific apoptosis within a therapeutic window. Hepatology (Baltimore, Md) 2007; 45: 649–658.

    Article  CAS  Google Scholar 

  27. Gieffers C, Kluge M, Merz C, Sykora J, Thiemann M, Schaal R et al. APG350 induces superior clustering of TRAIL receptors and shows therapeutic antitumor efficacy independent of cross-linking via Fcgamma receptors. Mol Cancer Ther 2013; 12: 2735–2747.

    Article  CAS  Google Scholar 

  28. Lemke J, von Karstedt S, Abd El Hay M, Conti A, Arce F, Montinaro A et al. Selective CDK9 inhibition overcomes TRAIL resistance by concomitant suppression of cFlip and Mcl-1. Cell Death Diff 2014; 21: 491–502.

    Article  CAS  Google Scholar 

  29. Lecis D, Mastrangelo E, Belvisi L, Bolognesi M, Civera M, Cossu F et al. Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization. Bioorg Med Chem 2012; 20: 6709–6723.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the patients and the staff at Imperial College Healthcare NHS Trust for providing and collecting the ovarian cancer ascites samples for this research. AMG655 was kindly provided by AMGEN Inc. (Thousand Oaks, CA, USA). We thank B Vogelstein and R Youle for providing cell lines. We also thank Dr C Kantari for technical advice and helpful discussions. This work has been funded by the Medical Research Council by providing a Clinical Research Training Fellowship for MHT (MC_EX_G0802342), Cancer Research UK, (C33499/A10950), Ovarian Cancer Action, and the Association for International Cancer Research. The SMAC mimetic compound SM083 (also known as SM 9a) was synthesised and kindly provided by P Seneci and L Manzoni.

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Author notes

  1. M H Tuthill & T Newsom-Davis

    Present address: 4Current address: National Centre for HIV Malignancies, Chelsea and Westminster Hospital, 369 Fulham Rd, London SW10, UK.,

  2. A Montinaro, J Zinngrebe, P Draber, S von Karstedt & H Walczak

    Present address: 5Current address: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.,

  3. K Prieske

    Present address: 6Current address: Department of Gynaecology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.,

  4. S Prieske

    Present address: 7Current address: University Hospital Hamburg-Eppendorf, Hamburg, Germany.,

  5. M H Tuthill and A Montinaro: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Medicine, Tumour Immunology Unit, Imperial College London, London, UK

    M H Tuthill, A Montinaro, J Zinngrebe, K Prieske, P Draber, S Prieske, T Newsom-Davis, S von Karstedt & H Walczak

  2. MRC Clinical Sciences Centre, Imperial College London, Du Cane Road, London, UK

    M H Tuthill

  3. Amgen Inc., Seattle, WA, USA

    J Graves

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  1. M H Tuthill
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Correspondence to H Walczak.

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Competing interests

HW is a named inventor on a patent underlying the development of AMG655. HW is a scientific advisor, co-founder and shareholder of Apogenix GmbH. The remaining authors declare no conflict of interest.

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Tuthill, M., Montinaro, A., Zinngrebe, J. et al. TRAIL-R2-specific antibodies and recombinant TRAIL can synergise to kill cancer cells. Oncogene 34, 2138–2144 (2015). https://doi.org/10.1038/onc.2014.156

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