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

TRAIL death receptors DR4 (Tumor necrosis factor receptor superfamily member 10A) and DR5 (Tumor necrosis factor receptor superfamily member 10B) are cell surface receptors that mediate the extrinsic apoptosis pathway upon binding to the TNF-related apoptosis-inducing ligand (TRAIL). These receptors contain an intracellular death domain that, when activated by ligand-induced trimerization, recruits the adaptor protein FADD and initiator caspases-8 or -10 to form the death-inducing signaling complex (DISC). This process triggers a proteolytic cascade leading to programmed cell death, which is notably selective for cancer cells over normal cells. In many malignancies, DR4 and DR5 are downregulated or their signaling is inhibited by factors like c-FLIP or decoy receptors, allowing tumors to evade immune surveillance. Therapeutic strategies targeting these receptors include recombinant human TRAIL (e.g., dulanermin) and various agonistic monoclonal antibodies (e.g., mapatumumab, conatumumab, and aplitabart). Biomarkers such as GALNT14, c-FLIP, and XIAP levels are being investigated to predict patient response and overcome resistance. Despite their potential, clinical development has faced challenges such as poor agonist potency, short half-lives, and the activation of pro-survival non-apoptotic pathways in resistant cells.

Other names

Death receptor 4Death receptor 5TRAIL receptor 1TRAIL receptor 2TNFRSF10ATNFRSF10BCD261CD262APO2KILLERTRICK2

Agonism of DR4 and/or DR5 to induce the extrinsic apoptotic pathway via FADD recruitment and Caspase-8/10 activation.