TY  - JOUR
A1  - Wajant, Harald
T1  - Molecular mode of action of TRAIL receptor agonists—common principles and their translational exploitation
T2  - Cancers
N2  - 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.
KW  - antibody
KW  - antibody fusion proteins
KW  - apoptosis
KW  - cancer therapy
KW  - cell death
KW  - death receptors
KW  - TNF superfamily
KW  - TNF receptor superfamily
KW  - TRAIL
Y1  - 2019
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/20183
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-201833
N1  - Zugriff gesperrt. Zugriff auf den Volltext erhalten Sie unter https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-202416
VL  - 11
IS  - 7
ER  -