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  • Review Article
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Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy

Key Points

  • Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a molecule belonging to the tumour necrosis factor (TNF) superfamily. In humans, two TRAIL receptors (TRAIL-R1 and TRAIL-R2) and in mice one receptor (mTRAIL-R) can signal apoptosis upon binding of TRAIL.

  • Induction of apoptosis is enabled through recruitment of the death-inducing signalling complex (DISC). This complex leads to activation of a caspase cascade.

  • TRAIL–TRAIL-R binding can also induce non-apoptotic signalling including via activation of nuclear factor-κB (NF-κB), p38, ERK, SRC and RAC1.

  • Mice deficient in TRAIL or mTRAIL-R are more susceptible to various cancers whereas conditional deletion of mTRAIL-R in Kras- driven cancers ameliorates disease progression. TRAIL–TRAIL-R blockade might therefore be a therapeutic option for patients with KRAS-mutated cancers.

  • TRAIL–TRAIL-R interaction on myeloid-derived suppressor cells in the tumour microenvironment can limit their lifespan and thereby tip the balance towards an antitumour immune environment. Hence, patients with an immunosuppressive cancer microenvironment might benefit from TRAIL-R agonistic therapy.

  • Clinical trials testing an untagged form of recombinant TRAIL, agonistic TRAIL-R1 or TRAIL-R2-specific antibodies or antibody derivatives with higher crosslinking capacity have not led to anticipated therapeutic benefit.

  • Preclinical approaches using therapeutic combinations comprising optimized TRAIL-R agonists and recently discovered powerful apoptosis sensitizers are, however, promising. Therefore, such novel pro-apoptotic combination therapies should be tested in clinical trials.

  • Several drugs, some of which have been approved by the US Food and Drug Administration, induce extrinsic apoptosis through autocrine engagement of the TRAIL–TRAIL-R pathway. Therefore, expression of TRAIL apoptosis pathway components, as well as lack of expression of inhibitors thereof, might be useful for patient selection in clinical trials testing the efficacy of such drugs.

Abstract

The discovery that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis of cancer cells without causing toxicity in mice has led to the in-depth study of pro-apoptotic TRAIL receptor (TRAIL-R) signalling and the development of biotherapeutic drug candidates that activate TRAIL-Rs. The outcome of clinical trials with these TRAIL-R agonists has, however, been disappointing so far. Recent evidence indicates that many cancers, in addition to being TRAIL resistant, use the endogenous TRAIL–TRAIL-R system to their own advantage. However, novel insight on two fronts — how resistance of cancer cells to TRAIL-based pro-apoptotic therapies might be overcome, and how the pro-tumorigenic effects of endogenous TRAIL might be countered — gives reasonable hope that the TRAIL system can be harnessed to treat cancer. In this Review we assess the status quo of our understanding of the biology of the TRAIL–TRAIL-R system — as well as the gaps therein — and discuss the opportunities and challenges in effectively targeting this pathway.

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Figure 1: Human and mouse TRAIL-receptor systems.
Figure 2: TRAIL-induced signalling pathways.
Figure 3: The influence of the TRAIL–TRAIL-R system on the cancer immune environment.
Figure 4: Proposed therapeutic concepts using the TRAIL–TRAIL-R system.

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Acknowledgements

The authors were supported by a Cancer Research UK (CRUK) programme grant (A17341), a Wellcome Trust Senior Investigator Award (096831/Z/11/Z), a European Research Council (ERC) advanced grant (294880) held by H.W., a CRUK Centre grant (515818), a CRUK Centre Network Accelerator Award on Cancer Immunotherapy (CITA) (525877), the Manchester–UCL CRUK Lung Cancer Centre of Excellence (522434), and the National Institute for Health Research University College London Hospitals Biomedical Research Centre. This Review is dedicated to the memory of our friend and collaborator Martin Leverkus.

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Correspondence to Henning Walczak.

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H.W. is a scientific adviser, co-founder and shareholder of Apogenix AG. The other authors declare no competing interests.

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Glossary

Type II transmembrane proteins

Defined by a single transmembrane domain, an amino terminus facing the cytosol and an extracellular carboxy terminus.

Glycocalyx

A dense coat of glycoproteins extending into the extracellular space that covers most cells.

Extrinsic apoptosis

A type of apoptosis in which caspase activation is triggered by death ligands binding to cell surface death receptors.

Apoptosome

A heptameric multiprotein complex that aids caspase activation during extrinsic and intrinsic apoptosis induction following mitochondrial outer membrane permeabilization.

Microprocessor complex

A protein complex that mediates maturation of microRNAs in the nucleus.

Nanobody

A therapeutic protein characterized by high-affinity variable domains of the heavy chain antibodies (VHH) derived from a camelid.

Anti-drug antibody (ADA) response

An adverse immune response to a therapeutic protein that can interfere with the drug pharmacokinetics, pharmacodynamics, safety and efficacy.

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von Karstedt, S., Montinaro, A. & Walczak, H. Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat Rev Cancer 17, 352–366 (2017). https://doi.org/10.1038/nrc.2017.28

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