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

The Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor system consists of two pro-apoptotic signaling receptors, TRAIL-R1 (Death receptor 4) and TRAIL-R2 (Death receptor 5), along with three decoy receptors that modulate signaling [1, 5]. Upon binding of the homotrimeric TRAIL ligand (TNFSF10), the pro-apoptotic receptors undergo trimerization and recruit the adaptor protein FADD and pro-caspase 8 to form the death-inducing signaling complex (DISC) [2, 16]. This assembly initiates the extrinsic apoptotic pathway, leading to the activation of executioner caspases and programmed cell death [7, 10]. A defining feature of this system is its ability to selectively induce apoptosis in malignant cells while sparing most normal tissues, making it a highly attractive target for oncology [3, 13]. However, clinical development of TRAIL-based therapies has faced significant hurdles, including the short half-life of recombinant ligands and the emergence of resistance mechanisms such as the upregulation of c-FLIP or decoy receptors [4, 6]. First-generation agents like dulanermin and various agonistic monoclonal antibodies (e.g., mapatumumab, conatumumab) showed limited efficacy in trials despite favorable safety profiles [11, 16]. Current research focuses on second-generation agonists with improved valency and pharmacokinetic properties, as well as combination therapies with sensitizing agents like proteasome inhibitors or chemotherapy to overcome resistance [13, 17].

Other names

Death receptor 4Death receptor 5DR4DR5TRAIL-R1TRAIL-R2TNFRSF10ATNFRSF10BCD261CD262Apo-2KillerTrick2

Agonism of pro-apoptotic TRAIL receptors (DR4 and DR5) to induce the extrinsic apoptotic pathway through the formation of the death-inducing signaling complex (DISC) and subsequent caspase activation [2, 16].