Cancer Immunology, Immunotherapy

, Volume 60, Issue 8, pp 1173–1180 | Cite as

Targeting the extrinsic apoptosis signaling pathway for cancer therapy

  • Thomas J. SayersEmail author
Focussed Research Review


The extrinsic apoptosis pathway is triggered by the binding of death ligands of the tumor necrosis factor (TNF) family to their appropriate death receptors (DRs) on the cell surface. One TNF family member, TNF-related apoptosis-inducing ligand (TRAIL or Apo2L), seems to preferentially cause apoptosis of transformed cells and can be systemically administered in the absence of severe toxicity. Therefore, there has been enthusiasm for the use of TRAIL or agonist antibodies to the TRAIL DR4 and DR5 in cancer therapy. Nonetheless, many cancer cells are very resistant to TRAIL apoptosis in vitro. Therefore, there is much interest in identifying compounds that can be combined with TRAIL to amplify its apoptotic effects. In this review, I will provide a brief overview of apoptosis signaling by TRAIL and discuss apoptosis-sensitizing agents, focusing mainly on the proteasome inhibitor bortezomib (VELCADE) and some novel sensitizers that we have recently identified. Alternative ways to administer TRAIL or DR agonist antibodies as therapeutic agents will also be described. Finally, I will discuss some of the gaps in our understanding of TRAIL apoptosis signaling and suggest some research directions that may provide additional information for optimizing the targeting of the extrinsic apoptosis pathway for future cancer therapy.


TRAIL Bortezomib Extrinsic apoptosis Proteasome inhibition Death receptors 



TNF-related apoptosis-inducing ligand


Cellular FLICE-inhibitory protein


Inhibitor of apoptosis protein


Fas-associated death domain


Death-inducing signaling complex


Second mitochondrial activator of caspases/direct IAP-binding protein with low pI



This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations implies endorsement by the US Government. This Research was supported [in part] by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Thanks to Alan Brooks, Candace Thompson, Richard Pompei, Drs Nancy Booth, and Curtis Henrich for their assistance with this work and Andrew Sayers for help with the artwork.


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Copyright information

© Springer-Verlag (Outside the USA) 2011

Authors and Affiliations

  1. 1.SAIC-Frederick, Inc., Laboratory of Experimental Immunology, Center for Cancer Research, Cancer and Inflammation ProgramNational Cancer InstituteFrederickUSA

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