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Molecular Mode of Action of TRAIL Receptor Agonists—Common Principles and Their Translational Exploitation

Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
Cancers 2019, 11(7), 954; https://doi.org/10.3390/cancers11070954
Received: 3 June 2019 / Revised: 28 June 2019 / Accepted: 2 July 2019 / Published: 7 July 2019
(This article belongs to the Special Issue TRAIL Signaling in Cancer Cells)
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptors TRAILR1/death receptor 4 (DR4) and TRAILR2/DR5 trigger cell death in many cancer cells but rarely exert cytotoxic activity on non-transformed cells. Against this background, a variety of recombinant TRAIL variants and anti-TRAIL death receptor antibodies have been developed and tested in preclinical and clinical studies. Despite promising results from mice tumor models, TRAIL death receptor targeting has failed so far in clinical studies to show satisfying anti-tumor efficacy. These disappointing results can largely be explained by two issues: First, tumor cells can acquire TRAIL resistance by several mechanisms defining a need for combination therapies with appropriate sensitizing drugs. Second, there is now growing preclinical evidence that soluble TRAIL variants but also bivalent anti-TRAIL death receptor antibodies typically require oligomerization or plasma membrane anchoring to achieve maximum activity. This review discusses the need for oligomerization and plasma membrane attachment for the activity of TRAIL death receptor agonists in view of what is known about the molecular mechanisms of how TRAIL death receptors trigger intracellular cell death signaling. In particular, it will be highlighted which consequences this has for the development of next generation TRAIL death receptor agonists and their potential clinical application. View Full-Text
Keywords: antibody; antibody fusion proteins; apoptosis; cancer therapy; cell death; death receptors; TNF superfamily; TNF receptor superfamily; TRAIL antibody; antibody fusion proteins; apoptosis; cancer therapy; cell death; death receptors; TNF superfamily; TNF receptor superfamily; TRAIL
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Wajant, H. Molecular Mode of Action of TRAIL Receptor Agonists—Common Principles and Their Translational Exploitation. Cancers 2019, 11, 954.

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Cancers, EISSN 2072-6694, Published by MDPI AG
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