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Overcoming Cancer Cell Resistance to Death Receptor Targeted Therapies

  • Chapter
Resistance of Cancer Cells to CTL-Mediated Immunotherapy

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 7))

  • 855 Accesses

Abstract

Death receptors (DRs) are promising targets for cancer therapies because of their ability to induce apoptosis in cancer cells. These receptors are characterized by an intracellular death domain, which transmits a death signal from their cognate ligands, including TNF-related apoptosis inducing ligand (TRAIL). Currently, multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL and agonistic antibodies to its receptors DR4 and DR5. Although the products have shown a tolerated safety profile in the completed phase 1 studies, a large number of cancer cell lines are found to be resistant to these agents, raising a concern about their clinical efficacy. This review provides an update of recent advances in understanding the molecular mechanisms involved in cancer cell resistance to DR4/DR5 targeted therapies. This information will be further discussed with respect to combinational strategies to overcome or bypass resistance mechanisms towards a better treatment outcome.

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Abbreviations

5-dAzaC:

5-Aza-2′-deoxycytidine

5-FU:

5-Fluorouracil

AE:

Adverse effects

BH:

Bcl-2 homology

c-FLIP:

Cellular FADD-like IL-1 beta-converting enzyme inhibitor protein

DISC:

Death inducing signaling complex

DLT:

Dose limiting toxicities

DR:

Death receptors

EGFR:

Epidermal growth factor receptor

FADD:

Fas-associated death domain

FOLFIRI:

Fololinic acid, fluorouracil, and irinotecan

FOLFOX:

Fololinic acid, fluorouracil, and oxiplatin

HER:

Human epidermal receptor

IAP:

Inhibitor of apoptosis proteins

IFN:

Interferon

IGFR:

Insulin-like growth factor receptor

MOA:

Mechanism of action

NSCLC:

Non-small cell lung cancer

PNET:

Primitive neuroectodermal

rhTRAIL:

Recombinant human TRAIL

SCLC:

Small cell lung cancer

siRNA:

Small interfering RNA

SMAC/DIABLO:

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

tBid:

Truncated Bid

TNFR:

Tumor necrosis factor

TRAIL:

TNF-related apoptosis inducing ligand

XIAP:

x Chromosome-linked inhibitor of apoptosis

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Acknowledgment

This work was partly supported by funding from the FDA/CDER Critical Path initiatives.

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  1. Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD, 20892, USA

    Julianne D. Twomey, William Hallett & Baolin Zhang

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  1. Julianne D. Twomey
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  2. William Hallett
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  3. Baolin Zhang
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Correspondence to Baolin Zhang .

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Editors and Affiliations

  1. Department of Microbiology, Immunology a, University of California at Los Angeles,, Los Angeles, California, USA

    Benjamin Bonavida

  2. Institut Gustave Roussy, Villejuif, France

    Salem Chouaib

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No Conflict of Interest/Disclaimer: The comments and discussions in this paper are based on our experimental data and a survey of the related scientific publications. They do not necessarily reflect the official views of the US Food and Drug Administration with respect to the development of the death receptor targeted therapies. The use of product names is for product identification purpose only and does not imply endorsement.

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Twomey, J.D., Hallett, W., Zhang, B. (2015). Overcoming Cancer Cell Resistance to Death Receptor Targeted Therapies. In: Bonavida, B., Chouaib, S. (eds) Resistance of Cancer Cells to CTL-Mediated Immunotherapy. Resistance to Targeted Anti-Cancer Therapeutics, vol 7. Springer, Cham. https://doi.org/10.1007/978-3-319-17807-3_10

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