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

Tumor necrosis factor receptor superfamily member 10A (DR4) and 10B (DR5) are transmembrane proteins that mediate the extrinsic pathway of apoptosis (Source: UniProt O00220, O14763). These receptors are activated upon binding to the TNF-related apoptosis-inducing ligand (TRAIL), which is primarily expressed by immune cells like natural killer cells and T cells. Binding induces receptor trimerization and the assembly of the death-inducing signaling complex (DISC), involving the recruitment of the adapter protein FADD and pro-caspase-8 (Source: PMID: 29330110). This molecular assembly triggers a proteolytic cascade of caspases that ultimately results in programmed cell death. Because DR4 and DR5 are often upregulated in various malignant cells while being minimally expressed or decoyed in healthy tissues, they are significant targets for selective cancer therapies. Therapeutic strategies have included recombinant human TRAIL variants and agonistic monoclonal antibodies designed to mimic the ligand's pro-apoptotic action. Despite promising preclinical data, clinical success has been hampered by the short half-life of first-generation agents and the presence of intrinsic or acquired resistance in many tumors. Recent drug development efforts focus on next-generation multivalent agonists and combination regimens to enhance signaling intensity and overcome resistance (Source: PMID: 31434151). Notable safety concerns include potential hepatotoxicity, which was observed with certain high-potency multivalent DR5 agonists in early-phase trials.

Other names

TRAIL-R1TRAIL-R2Death receptor 4Death receptor 5TNFRSF10ATNFRSF10BCD261CD262APO2KILLERTRICK2

Agonism of DR4 and DR5 induces receptor trimerization and the subsequent assembly of the death-inducing signaling complex (DISC), which recruits FADD and pro-caspase-8 to initiate the caspase cascade and trigger programmed cell death (Source: PMID: 31434151).