Death Receptors at the Molecular Level: Therapeutic Implications

Abstract

Abstract Since the discovery that activation of a subset of cell surface receptors within the tumour necrosis factor (TNF) receptor superfamily could trigger apoptosis, several members of the TNF superfamily including TNF, CD95L and TNF‐related apoptosis‐inducing ligand ( TRAIL ) have been identified as potentially important targets for cancer therapy. Although systemic administration of TNF or CD95L causes severe toxic side effects, thus hampering their potential application in the clinic, the discovery of TRAIL and its cognate death receptors, TRAIL‐R1 and TRAIL‐R2 , have provided an exciting new opportunity for selective targeting of tumour cells. TRAIL receptor activation has emerged as the most promising approach for death receptor‐targeted therapy while inducing minimal toxicity in the majority of normal cells. Intensive research, including detailed analysis of death ligand–death receptor pairs at the structural level have enabled the development of several different approaches aimed at selective targeting of TRAIL‐R1/TRAIL‐R2 in tumour cells. Key concepts: Death receptor ligands, including CD95L and tumour necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL), are potent stimulators of apoptosis. Unlike TNF and CD95L, which on systemic administration exhibit toxicity, TRAIL is selectively toxic to tumour cells while sparing most normal cells. Although the molecular basis for the tumour selective activity of TRAIL remains to be fully defined, the TRAIL pathway is an attractive therapeutic target for the treatment of cancer. Key discoveries at the structural level have revealed several important features of the molecular interaction between TRAIL and its cognate death receptors, TRAIL‐R1/ TRAIL‐R2, that are critical for TRAIL‐receptor triggering of apoptosis. Based on structural and predicted models of TRAIL in complex with TRAIL‐R1/ TRAIL‐R2, recombinant TRAIL, receptor‐selective TRAIL variants, as well as anti‐TRAIL receptor antibodies have been developed, thus providing the opportunity to target both receptors or selectively target either TRAIL‐R1 or TRAIL‐R2 in tumour cells. In preclinical trials, recombinant forms of TRAIL and agonistic anti‐TRAIL receptor antibodies can synergise with chemotherapeutic drugs and novel chemotherapeutic agents to effectively kill TRAIL‐resistant primary tumour cells. Although early phase clinical trials indicate these agents can be delivered safely and are generally well tolerated as monotherapies, the most attractive use of these agents and their greatest promise for further clinical development will be when used in combination with other cancer treatments.