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Tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAIL receptor(s))

Target: TRAIL receptor(s)
Molecular classification: Receptor, Death receptor, Transmembrane receptor, Tumor necrosis factor receptor superfamily member

Overview

TRAIL receptors are members of the tumor necrosis factor (TNF) receptor superfamily that mediate the potent pro-apoptotic effects of the ligand TRAIL. There are multiple membrane-bound (DR4/TRAIL-R1, DR5/TRAIL-R2, DcR1/TRAIL-R3, DcR2/TRAIL-R4) and one soluble (OPG) receptors. DR4 and DR5 possess a functional intracellular "death domain" that initiates apoptosis upon ligand binding, whereas the others act as decoys or modulators of apoptotic signaling. These receptors are important regulators of immune cell-mediated tumor surveillance and are being actively targeted in anticancer drug development; however, therapeutic use is hindered by variable receptor expression, emergence of resistance, and some on-target toxicity in normal tissues

Other names: TRAIL receptorTRAIL-Rdeath receptor 4 (DR4)TRAIL-R1TNFRSF10ACD261APO2death receptor 5 (DR5)TRAIL-R2TNFRSF10BCD262KILLERTRICK2ZTNFR9decoy receptor 1 (DcR1)TRAIL-R3TNFRSF10CTRIDdecoy receptor 2 (DcR2)TRAIL-R4TNFRSF10DTRUNDDosteoprotegerin (OPG)

Mechanism of action

Drugs targeting TRAIL receptors typically induce apoptosis via extrinsic pathway activation (death domain, FADD, and caspase-8 recruitment), or block/decoy signaling in the case of antagonists or decoy receptor-targeting agents

Biological functions

Apoptosis inductionCell deathSignal transductionImmune responseNon-apoptotic signaling (e.g., inflammation, NF-κB activation in the case of decoy receptors)

Disease associations

Cancer (tumor apoptosis, immunosurveillance)InflammationInfectionCardiovascular diseasesAutoimmune diseases

Safety considerations

Selectivity for tumor cells is a challenge (normal cell toxicity in clinical trials)liver toxicity (noted in some agonist trials)possible induction of inflammationemergence of resistance via decoy receptor upregulation or loss/downregulation of death receptors in tumors

Interacting drugs

Dulanermin (recombinant human TRAIL)

6 more in the full profile.

Biomarkers

Expression levels of DR4 (TRAIL-R1) and DR5 (TRAIL-R2) in tumor tissuepresence of p53 mutations (which regulate DR4/DR5 expression)decoy receptor expression as markers of resistance

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