Tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (alternatively: Tumor necrosis factor-related apoptosis-inducing ligand receptor 2) (TRAIL-R1 (DR4), TRAIL-R2 (DR5))

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway mediates the extrinsic apoptosis program via its death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5), which upon ligand binding recruit FADD, activate caspase-8/10, and initiate the cascade leading to programmed cell death. These receptors are of particular therapeutic interest because TRAIL preferentially induces apoptosis in transformed or cancerous cells, sparing most normal tissues. TRAIL pathway agonists and recombinant proteins have been pursued for cancer therapy, but face limitations from short half-life, development of resistance, and in some cases tolerability concerns. The expression levels and function of the death receptors as well as decoy receptors such as DcR1, DcR2, and OPG are important determinants of activity and resistance.

Other names

TRAIL receptor 1 (DR4)TRAIL receptor 2 (DR5)Death receptor 4 (DR4)Death receptor 5 (DR5)TNFRSF10A (TRAIL-R1 gene symbol)TNFRSF10B (TRAIL-R2 gene symbol)Apo2Apo2L receptor

Activation of TRAIL receptors by ligand or agonist antibodies leading to death-inducing signaling complex (DISC) formation, caspase-8/10 activation, and execution of apoptosis (extrinsic pathway). Synergy with proteasome inhibitors or other sensitizers to overcome tumor resistance to TRAIL.