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Updated: Apr 15, 2026

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Spatial dynamics of TRAIL death receptors in cancer cells

Julianne D Twomey1, Su-Ryun Kim1, Liqun Zhao1

  • 1Division of Biotechnology Review and Research IV, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, United States.

Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
|April 5, 2015
PubMed

Insights

TNF-related apoptosis inducing ligand (TRAIL) selectively targets cancer cells. Understanding TRAIL death receptor dynamics is key to overcoming drug resistance and improving cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • TNF-related apoptosis inducing ligand (TRAIL) induces cancer cell apoptosis, with clinical trials evaluating recombinant human TRAIL (rhTRAIL) and DR4/DR5 antibodies.
  • Early studies show a good safety profile for TRAIL-based therapies, but therapeutic potential is limited by drug resistance.
  • Tumor drug resistance to TRAIL is often linked to reduced surface expression of death receptors (DRs) 4 and 5, even with normal total protein levels.

Purpose of the Study:

  • To review recent findings on the dynamic expression of TRAIL death receptors.
  • To highlight regulatory mechanisms influencing TRAIL receptor surface presentation.
  • To identify strategies for overcoming TRAIL resistance in cancer therapy.

Main Methods:

  • Review of current literature on TRAIL receptor biology and cancer drug resistance.
  • Analysis of regulatory roles of endocytosis, autophagy, and Ras GTPase signaling in TRAIL receptor expression.
  • Synthesis of information on predictive biomarkers and combination drug development.

Main Results:

  • Dynamic regulation of TRAIL death receptor expression on cancer cell plasma membranes is critical for apoptosis induction.
  • Endocytosis, autophagy, and Ras GTPase signaling significantly influence surface DR4/DR5 levels.
  • Deficiency of surface DR4/DR5 is a key mechanism of TRAIL resistance, independent of other apoptotic pathways.

Conclusions:

  • Understanding the dynamic regulation of TRAIL death receptors is crucial for predicting tumor response to TRAIL-targeted therapies.
  • Identifying novel predictive biomarkers for TRAIL sensitivity is essential.
  • Developing combination strategies targeting receptor dynamics may overcome TRAIL resistance and enhance therapeutic efficacy.
Keywords:
Death receptorsDrug resistanceSurface expressionTRAILTargeted cancer therapy

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