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Targeting death-inducing receptors in cancer therapy

Abstract

Deregulated cell death pathways may lead to the development of cancer, and induction of tumor cell apoptosis is the basis of many cancer therapies. Knowledge accumulated concerning the molecular mechanisms of apoptotic cell death has aided the development of new therapeutic strategies to treat cancer. Signals through death receptors of the tumor necrosis factor (TNF) superfamily have been well elucidated, and death receptors are now one of the most attractive therapeutic targets in cancer. In particular, DR5 and DR4, death receptors of TNF-related apoptosis-inducing ligand (TRAIL or Apo2L), are interesting targets of antibody-based therapy, since TRAIL may also bind decoy receptors that may prevent TRAIL-mediated apoptosis, whereas TRAIL ligand itself selectively induces apoptosis in cancer cells. Here, we review the potential therapeutic utility of agonistic antibodies against DR5 and DR4 and discuss the possible extension of this single-antibody-based strategy when combined with additional modalities that either synergizes to cause enhanced apoptosis or further engage the cellular immune response. Rational design of antibody-based therapies combining the induction of tumor cell apoptosis and activation of tumor-specific adaptive immunity enables promotion of distinct steps of the antitumor immune response, thereby enhancing tumor-specific lymphocytes that can eradicate TRAIL/DR5-resistant mutating, large established and heterogeneous tumors in a manner that does not require the definition of individual tumor-specific antigens.

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Abbreviations

ADCC:

antibody-dependent cellular cytotoxicity

APCs:

antigen-presenting cells

CDC:

complement-dependent cytotoxicity

DCs:

dendritic cells

EGFRs:

epidermal growth factor receptors

mAbs:

monoclonal antibodies

rTRAIL:

recombinant TRAIL

TRAIL:

TNF-related apoptosis-inducing ligand

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Acknowledgements

This work is supported by the Ministry of Education, Science and Culture, Japan. JS is supported by a fellowship from the Canadian Institutes of Health Research (CIHR). MJS is supported by a National Health and Medical Research Council of Australia Program Grant and Research Fellowship. We thank the Susan G Komen Breast Cancer Foundation for their funding support.

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Takeda, K., Stagg, J., Yagita, H. et al. Targeting death-inducing receptors in cancer therapy. Oncogene 26, 3745–3757 (2007). https://doi.org/10.1038/sj.onc.1210374

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