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

The TRAIL receptors DR4 (Tumor necrosis factor receptor superfamily member 10A) and DR5 (Tumor necrosis factor receptor superfamily member 10B) are key mediators of the extrinsic apoptosis pathway (Source 1.2.1). Upon binding to the Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), these receptors trimerize and recruit the adaptor protein FADD and pro-caspase-8 to form the death-inducing signaling complex (DISC), initiating a caspase cascade that leads to programmed cell death (Source 1.3.1). A defining feature of these receptors is their ability to selectively induce apoptosis in cancer cells while sparing most normal tissues, making them attractive targets for oncology (Source 1.2.3). Therapeutic strategies have included recombinant human TRAIL (e.g., dulanermin) and agonistic monoclonal antibodies such as mapatumumab and lexatumumab (Source 1.3.1). However, clinical development has faced challenges including tumor resistance mediated by decoy receptors or anti-apoptotic proteins like c-FLIP, as well as the limited potency of early bivalent antibodies (Source 1.3.3, 1.3.4). Current research is focused on next-generation multivalent agonists and combination therapies to enhance therapeutic efficacy and overcome resistance mechanisms (Source 1.2.1).

Other names

TRAIL-R1TRAIL-R2CD261CD262Death receptor 4Death receptor 5Apo2KillerTNFRSF10ATNFRSF10BTRICK2TRICK2AZTNFR9

Agonism of DR4 and DR5 induces receptor trimerization and the assembly of the death-inducing signaling complex (DISC), which activates the extrinsic apoptotic pathway via caspase-8 and caspase-10.