Tumor necrosis factor receptor superfamily member 10A and 10B (DR4/DR5)

Death Receptor 4 (DR4/TNFRSF10A) and Death Receptor 5 (DR5/TNFRSF10B) are transmembrane proteins belonging to the tumor necrosis factor (TNF) receptor superfamily that mediate the extrinsic apoptosis pathway (UniProt O00220, O14763). These receptors are activated upon binding to the TNF-related apoptosis-inducing ligand (TRAIL), leading to the recruitment of the adapter protein FADD and the initiator protease pro-caspase-8 to form the death-inducing signaling complex (DISC) (PubMed: 25103562). This activation triggers a downstream caspase cascade that results in programmed cell death. DR4 and DR5 are attractive therapeutic targets because they are often overexpressed in a wide variety of cancers, including colon, lung, and breast cancer, while being minimally expressed in most normal tissues (PubMed: 18473300). Clinical strategies have utilized recombinant human TRAIL (e.g., dulanermin) or agonistic monoclonal antibodies (e.g., mapatumumab and conatumumab) to selectively induce apoptosis in tumor cells (NCI Drug Dictionary). Additionally, small molecules like ONC201 have been developed to induce the expression of the TRAIL ligand itself to trigger these receptors (PubMed: 23388663). However, therapeutic success has been limited by the short half-life of these agents and the presence of resistance mechanisms, such as the expression of decoy receptors (DcR1 and DcR2) or the anti-apoptotic protein c-FLIP (PubMed: 30333267). Current research is focused on multi-valent agonists and combination therapies to overcome these challenges and enhance clinical efficacy.

Other names

Death receptor 4Death receptor 5TRAIL-R1TRAIL-R2TNFRSF10ATNFRSF10BCD261CD262APO2KILLERTRICK2ZTNFR10

Agonism of DR4 and DR5 receptors to trigger the extrinsic apoptotic pathway via the formation of the death-inducing signaling complex (DISC) and activation of caspase-8 (PubMed: 25103562).