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Human Cancer Resistance to Trail-Apoptotic Pathway-Targeted Therapies

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Molecular Mechanisms of Tumor Cell Resistance to Chemotherapy

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 1))

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Abstract

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) mediates innate and adaptive immunity against the tumorigenesis and tumor progression. TRAIL binds its two death receptors, DR4 and DR5, which activate intracellular pathway of apoptosis for self destruction of tumor cells. To target this apoptotic pathway, recombinant human TRAIL and monoclonal antibodies to DR4 and DR5 have been generated as TRAIL agonists for clinical cancer therapies. A number of TRAIL agonists have passed drug safety evaluation in phase I trials; however, the data from phase II trials thus far are disappointing: TRAIL agonists either in monotherapy or combination have failed to show clinical antitumor activity. In this chapter, we will provide a historic review of the advances and the challenges in the development of TRAIL agonists for clinical treatment of human cancers.

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Abbreviations

Apaf1:

Apoptotic protease activating factor 1

Bid:

Bcl-2 inhibitory BH3-domain-containing protein

tBid:

truncated Bid

cFLIP:

cellular FADD-like interleukin-1β-converting enzyme-like inhibitory protein

CYLD:

cylindromatosis

CUL3:

Cullin 3

CDDO:

Cyano-3,12-dioxooleana-1,9-dien-28-oic acid

CDDO-Me:

CDDO-methyl ester

CDDO-IM:

CDDO-imidazolide

CCNU:

1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea

DcR:

Decoy receptor

DED:

death effector domain

DD:

death domain

DISC:

death-inducing signaling complex

DR:

death receptor

DIABLO:

direct inhibitor of apoptosis binding protein with low pI

DFF45:

DNA fragmentation factor 45

DUB:

deubiquitinating

ERK 1/2:

extracellular signal-regulated kinase 1/2

FADD:

Fas-associated death domain

FasL:

Fas ligand

FLICE:

FADD-like interleukin-1β-converting enzyme

GPI:

glycosyl phosphatidylinositol

IAP:

inhibitors of apoptosis proteins

cIAP:

cellular inhibitors of apoptosis proteins

IKKγ:

inhibitor of κB (IκB) kinase γ

mAb:

monoclonal antibody

mTOR:

mammalian target of rapamycin

NHL:

non-Hodgkin lymphoma

NSCLC:

non-small cell lung carcinoma

NF-κB:

nuclear factor-κB

OTU:

N-terminal ovarian tumor domain

PEA-15:

phosphopritein enriched in astrocytes-Mr 15,000

PED:

phosphoprotein enriched in diabetes

PLAC:

preligand assembly complex

PI3K:

phosphatidylinositide-3-kinase

rhTRAIL:

recombinant human TRAIL

RIP:

receptor interacting protein

Smac:

second mitochondria-derived activator of caspase

TNF:

tumor necrosis factor

TNFSF:

TNF ligand superfamily member

TNFR:

TNF receptor

TRAIL:

tumor necrosis factor-related apoptosis inducing ligand

TRAILR:

TRAIL receptor

TRADD:

TNFR1-associated death domain

TRAF2:

TNFR-associated factor 2

TNFAIP3:

TNFα-induced protein 3

TNFSF15:

TNF ligand superfamily member 15

UB:

ubiquitin

XIAP:

X-linked inhibitor of apoptosis

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Acknowledgments

The work in our laboratory has been supported in part by grants from the Alberta Heritage Foundation for Medical Research, Canadian Institutes of Health Research, National Cancer Institute of Canada, Georgia Cancer Coalition and National Institutes of Health of the United States.

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No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Anita C. Bellail

  2. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 1365-C Clifton Road NE, Atlanta, GA, 30322, USA

    Chunhai Hao

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  1. Anita C. Bellail
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  2. Chunhai Hao
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Correspondence to Chunhai Hao .

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Editors and Affiliations

  1. Dept. Microbiology, Immunology &, Molecular Genetics, University of California, Los Angeles, Charles E. Young Dr. E. 609, Los Angeles, 90095, California, USA

    Benjamin Bonavida

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Bellail, A.C., Hao, C. (2013). Human Cancer Resistance to Trail-Apoptotic Pathway-Targeted Therapies . In: Bonavida, B. (eds) Molecular Mechanisms of Tumor Cell Resistance to Chemotherapy. Resistance to Targeted Anti-Cancer Therapeutics, vol 1. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7070-0_11

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