TRAIL receptor signaling and therapeutics

Expert Opin Ther Targets. 2010 Oct;14(10):1091-108. doi: 10.1517/14728222.2010.519701.

Abstract

Importance of the field: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptotic cell death in a variety of tumor cells by engaging specific death receptors, TRAIL-R1 and TRAIL-R2, while having low toxicity towards normal cells. There is interest in cancer therapy inducing cell death by activation of the death-receptor-mediated apoptotic pathway while avoiding decoy-receptor-mediated neutralization of the signal. This has led to the development of a number of receptor-specific TRAIL-variants and agonistic antibodies. Some of these soluble recombinant TRAIL and agonist antibodies targeting TRAIL-R1 and/or TRAIL-R2 are progressing in clinical trials. In addition, TRAIL-resistant tumors can be sensitized to TRAIL by a combination of TRAIL or agonistic antibodies with chemotherapeutic agents, targeted small molecules or irradiation.

Areas covered in this review: Recent advances in developing TRAIL or its agonist receptor antibodies in cancer therapy. We also discuss combination therapies in overcoming TRAIL resistance in cancer cells.

What the reader will gain: Knowledge of current clinical trials, the promise and obstacles in the future development of therapies affecting TRAIL signaling pathways.

Take home message: Cancer therapeutics targeting the TRAIL/TRAIL receptor signaling pathway hold great promise for molecularly targeted pro-apoptotic anti-cancer therapy.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Clinical Trials as Topic
  • Combined Modality Therapy
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Signal Transduction / drug effects*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*

Substances

  • Antineoplastic Agents
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand