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. 2018;3(3):197-204.
doi: 10.1080/23808993.2018.1476062. Epub 2018 May 28.

TRAIL pathway targeting therapeutics

Marie D Ralff  1   2 , Wafik S El-Deiry  2
Affiliations

TRAIL pathway targeting therapeutics

Marie D Ralff et al. Expert Rev Precis Med Drug Dev. 2018.

Abstract

Introduction: Despite decades of focused research efforts, cancer remains a significant cause of morbidity and mortality. Tumor necrosis factor(TNF)-related apoptosis-inducing ligand (TRAIL) is capable of inducing cell death selectively in cancer cells while sparing normal cells.

Areas covered: In this review, the authors cover TRA therapy and strategies that have been undertaken to improve their efficacy, as well as unconventional approaches to TRAIL pathway activation including TRAIL-inducing small molecules. They also discuss mechanisms of resistance to TRAIL and the use of combination strategies to overcome it.

Expert commentary: Targeting the TRAIL pathway has been of interest in oncology, and although initial clinical trials of TRAIL receptor agonists (TRAs) showed limitations, novel approaches represent the future of TRAIL-based therapy.

Keywords: Apoptosis; DISC; Imipridone; TRAIL; TRAIL-R agonist; apoptosome; atrimer; cancer.

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Figures

Figure 1:
Figure 1:. Signaling pathways linking the TRAIL ligand to apoptosis.
TRAIL binds to its cell surface receptors DR4 and DR5 as a trimer. Receptor clustering and recruitment of FADD to intracellular the death domains starts formation of the DISC. Association of pro-caspase-8 finalizes DISC formation. Caspase-8 is cleaved to its active form. In type I cells, caspase-8 cleavage will directly cleave effector caspases 3, 6, and 7, triggering apoptosis. In type II cells, a secondary signal through the mitochondria is required. Caspase-8 will cleave Bcl-2 family protein Bid to its truncated form, tBid. This enables permeabilization of the mitochondrial outer membrane and release of cytochrome c into the cytosol. Pro-caspase-9 will be activated and go on to cleave effector caspases 3,6, and 7, leading to the induction of apoptosis.
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