Death Receptors at the Molecular Level: Therapeutic Implications

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.

Keywords: apoptosis; CD95; TRAIL; TRAIL‐R1/R2; X‐ray crystallography; cancer therapy

Figure 1.

Potential Therapeutic approaches to target TRAIL death receptor activation. The main types of TRAIL receptor agonists discussed in this article include ligand‐ and antibody‐based protein agents which induce apoptosis via TRAIL receptor‐mediated activation of the caspase cascade. Recombinant human Apo2L/TRAIL interacts with the death receptors, TRAIL‐R1 and TRAIL‐R2 (as well as the decoy receptors, TRAIL‐R3/R4), whereas receptor‐selective rhTRAIL variants and the monoclonal agonist antibodies are monospecific for either TRAIL‐R1 or TRAIL‐R2 (see text and Table for further detail).

Figure 2.

Crystal structure of the complex between rhApo2L/TRAIL and the extracellular domain of TRAIL‐R2. The rhApo2L/TRAIL trimer is shown as a ribbon rendering in gradations of blue, and the three receptors are rendered as tubes in yellow and orange colours. The zinc atom that coordinates the sulfhydryl groups of three unpaired cysteines, located at position 230 of each subunit, is shown in green. β strands and relevant loops are labelled (see text for further detail). (a) Side view. In this orientation, the membrane of the receptor‐containing cell is at the bottom of the figure. (b) Axial view. View down the 3‐fold axis of the complex, perpendicular to (a) (Hymowitz et al., ). Reproduced by permission of Elsevier (Cell Press).

Figure 3.

Model of TRAIL/TRAIL‐R1 complex and crystal structure of TRAIL/TRAIL‐R2 complex. (a) Role of TRAIL Asn‐199 in TRAIL (yellow)/TRAIL‐R1 (cyan)/TRAIL‐R2 (green) interactions. Hydrogen bond present with both TRAIL‐R1 and TRAIL‐R2 (black dashed line), and that present with only TRAIL‐R2 (red dashed line) is indicated. The loss of these hydrogen bonds with the TRAIL substitution N199V is also illustrated. (b) Role of TRAIL Tyr‐189 in TRAIL (yellow)/TRAIL‐R1/R2 (green) interactions. Hydrogen bond from this tyrosine to the conserved glutamate in TRAIL‐R1/R2 (dashed line) is indicated. Residues in TRAIL involved in hydrophobic interactions with Tyr‐189, that is, interactions lost in Y189A‐substituted TRAIL, are also shown (see text for further detail) (MacFarlane et al., ). Reproduced by permission of American Association for Cancer Research.

Figure 4.

Crystal structure of the Apomab Fab fragment in complex with the TRAIL‐R2 extracellular domain. (a) Apomab binds at the junction between CRD2 and CRD3. TRAIL‐R2 (brown, yellow and orange) and the Apomab Fab (light chain blue and heavy chain red) are shown as molecular interfaces. (b) Apo2L/TRAIL (blue) and Apomab (red) bind to overlapping yet distinct sites on TRAIL‐R2 (yellow). The structure of the Apomab Fab/TRAIL‐R2 complex is overlaid on the previously solved Apo2L /TRAIL‐R2 complex (see Figure ). For clarity, only one copy of TRAIL‐R2 is shown. Additional copies of TRAIL‐R2 that would bind at the Apo2L/TRAIL monomer–monomer interfaces are shown as yellow backbone ribbons (Adams et al., ). Reproduced by permission of Nature Publishing Group.

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Further Reading

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Ashkenazi A (2008) Directing cancer cells to self‐destruct with pro‐apoptotic receptor agonists. Nature Review of Drug Discovery 7: 1001–1012.

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MacFarlane, Marion(Dec 2009) Death Receptors at the Molecular Level: Therapeutic Implications. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021998]