Proapoptotic DR4 and DR5 signaling in cancer cells: toward clinical translation

Curr Opin Cell Biol. 2010 Dec;22(6):837-44. doi: 10.1016/j.ceb.2010.08.001. Epub 2010 Aug 31.

Abstract

Proapoptotic receptor agonists (PARAs) targeting death receptors (DRs) 4 and 5 hold promise for cancer therapy based on their selective ability to kill malignant versus healthy cells. Emerging clinical results have confirmed that DR4/5 PARAs are relatively well-tolerated and suitable for further investigation. Given that some cancer cell lines and models are not sensitive to PARAs, it is important to develop strategies to identify what specific types of tumor cells may be most responsive to PARA-based therapy and how to overcome apoptosis resistance mechanisms in tumors. Here we review the molecular and biological determinants of responsiveness to PARAs in cancer cells, and discuss the potential for predictive biomarkers and drug combination strategies to maximize the anti-tumor activity of these agents.

Publication types

  • Review

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Cell Membrane / metabolism
  • Humans
  • Mitochondria / metabolism
  • Neoplasms / metabolism*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Signal Transduction / physiology*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism

Substances

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