Death receptor agonist therapies for cancer, which is the right TRAIL?

Cytokine Growth Factor Rev. 2014 Apr;25(2):185-93. doi: 10.1016/j.cytogfr.2013.12.009. Epub 2013 Dec 24.


The activation of cell-surface death receptors represents an attractive therapeutic strategy to promote apoptosis of tumor cells. Several investigational therapeutics that target this extrinsic pathway, including recombinant human Apo2L/TRAIL and monoclonal agonist antibodies directed against death receptors-4 (DR4) or -5 (DR5), have been evaluated in the clinic. Although Phase 1/1b studies provided encouraging preliminary results, findings from randomized Phase 2 studies failed to demonstrate significant clinical benefit. This has raised multiple questions as to why pre-clinical data were not predictive of clinical response. Results from clinical studies and insight into why current agents have failed to yield robust responses are discussed. In addition, new strategies for the development of next generation death receptor agonists are reviewed.

Keywords: Apo2L/TRAIL; Apoptosis; Cancer; Death receptor.

Publication types

  • Review

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Apoptosis / drug effects
  • Apoptosis / immunology
  • Humans
  • Neoplasms / drug therapy
  • Receptors, Death Domain / agonists*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / immunology*
  • Receptors, Tumor Necrosis Factor / immunology*
  • Recombinant Proteins / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Treatment Failure


  • Antibodies, Monoclonal
  • Receptors, Death Domain
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFRSF21 protein, human
  • TNFSF10 protein, human