On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics

Oncogene. 2013 Mar 14;32(11):1341-50. doi: 10.1038/onc.2012.164. Epub 2012 May 14.


Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic antibodies against TRAIL death receptors (DR) kill tumor cells while causing virtually no damage to normal cells. Several novel drugs targeting TRAIL receptors are currently in clinical trials. However, TRAIL resistance is a common obstacle in TRAIL-based therapy and limits the efficiency of these drugs. In this review article we discuss different mechanisms of TRAIL resistance, and how they can be predicted and therapeutically circumvented. In addition, we provide a brief overview of all TRAIL-based clinical trials conducted so far. It is apparent that although the effects of TRAIL therapy are disappointingly modest overall, a small subset of patients responds very well to TRAIL. We argue that the true potential of targeting TRAIL DRs in cancer can only be reached when we find efficient ways to select for those patients that are most likely to benefit from the treatment. To achieve this, it is crucial to identify biomarkers that can help us predict TRAIL sensitivity.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • Humans
  • Models, Biological
  • Neoplasms / diagnosis*
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Prognosis
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • TNF-Related Apoptosis-Inducing Ligand / administration & dosage*
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / therapeutic use
  • Treatment Outcome


  • TNF-Related Apoptosis-Inducing Ligand