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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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Resistance to TRAIL in non-transformed cells is due to multiple redundant pathways

M van Dijk1, A Halpin-McCormick, T Sessler

  • 1Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway, Ireland.

Cell Death & Disease
|July 6, 2013
PubMed

Insights

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in normal cells is redundant, involving multiple proteins. Targeting single resistance pathways in tumour cells offers a safe therapeutic window for TRAIL-based therapies.

Area of Science:

  • Cellular and Molecular Biology
  • Cancer Research
  • Immunology

Background:

  • Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis selectively in tumor cells, not normal cells.
  • Developing TRAIL-sensitizing agents faces challenges due to incomplete understanding of TRAIL resistance mechanisms in non-malignant cells.
  • Unpredictable toxicity may arise if TRAIL sensitizers affect normal cells.

Purpose of the Study:

  • To systematically analyze the mechanisms of TRAIL resistance in non-transformed cells.
  • To understand the differences in TRAIL resistance mechanisms between tumor and non-transformed cells.
  • To identify potential therapeutic strategies for selective tumor cell sensitization.

Main Methods:

  • Systematic analysis of TRAIL resistance mechanisms in non-transformed cells.
  • Identification and quantification of key anti-apoptotic proteins (cFLIP, Bcl-2, XIAP).
  • Comparison of resistance pathways in non-transformed cells versus tumor cell lines.

Main Results:

  • Cellular FLICE-like inhibitory protein (cFLIP), B-cell lymphoma 2 (Bcl-2) proteins, and X-linked inhibitor of apoptosis protein (XIAP) independently confer TRAIL resistance.
  • Non-transformed cells exhibit redundant TRAIL resistance pathways, requiring deficiency in multiple proteins for sensitivity.
  • Tumor cells often rely on a single overexpressed resistance protein, with its inhibition sufficient to induce TRAIL sensitivity.

Conclusions:

  • Redundant anti-apoptotic pathways in non-transformed cells create a safety margin for TRAIL-based therapies.
  • Targeting single, non-redundant resistance mechanisms in tumor cells allows for selective sensitization.
  • This approach may enable safer and more effective TRAIL-based combination therapies.

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