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Cell Signaling and Resistance to Immunotoxins

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Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 6)

Abstract

The use of toxic plant or microbial proteins or polypeptides as immunotoxins has been a long-pursued strategy to increase the efficacy of targeted anti-cancer therapeutics. However, although these toxins can be highly potent, resistance has repeatedly been observed. Resistance to immunotoxin scan occur because of neutralizing antibodies or limited tumor cell access but also because of protective cellular signaling events in cancer cells. An increasing number of preclinical studies indicate that the latter form of resistance can be caused by a variety of mechanisms that either pre-exist because of genetic or epigenetic alterations or are induced by the immunotoxin itself, including modulation of cell surface expression of target antigens, altered trafficking or cleavage of toxin molecules, reduced synthesis of modified amino acid residues that are required for the toxin’s inhibition of protein synthesis, inhibited caspase activation or activation of other pro-survival pathways, and perhaps activation of drug transporter proteins. While the clinical relevance of these potential resistance mechanisms remains to be demonstrated in future studies, they provide a conceptual framework for cellular resistance to immunotoxins, and may form the basis for the development of rational strategies aimed at improving immunotoxin-based cancer therapy.

Keywords

Antibody Cancer Cellular Immunotherapy Immunotoxin Resistance Targeted Therapeutic Toxin 

Abbreviations

Bcl-2

B-cell lymphoma-2

cAMP

Cyclic AMP

CSEL1/CAS

Cellular apoptosis susceptibility gene

DT

Diphtheria toxin

EF-1

Elongation factor-1

EF-2

Elongation factor-2

IAP

Inhibitor of apoptosis protein

IFNγ

Interferon gamma

IGF

Insulin like growth factor

IL-1α

Interleukin:1 alpha

IL-3

Interleukin-3

IL-4

Interleukin-4

JNK

C-Jun NH2-terminal kinase

NAD

Nicotinamide adenine dinucleotide

NRG1-β1

Neuregulin:1 beta1

PARP

Poly (ADP) ribose polymerase

PKA

Protein kinase A

PKC

Protein kinase C

PE

Pseudomonas exotoxin A

PI3K

Phosphatidylinositol 3-kinase

rRNA

Ribosomal RNA

TNFα

Tumor necrosis factor alpha

TRAIL

TNF related apoptosis-inducing ligand

TWEAK

TNF like weak inducer of apoptosis

XIAP

X-linked inhibitor of apoptosis protein

Notes

Acknowledgements

The author is a recipient of an ‘A’ Award from the Alex’s Lemonade Stand Foundation and is a Leukemia & Lymphoma Society Scholar in Clinical Research.

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleUSA
  2. 2.Department of Medicine/Division of HematologyUniversity of Washington School of MedicineSeattleUSA
  3. 3.Department of EpidemiologyUniversity of Washington School of Public HealthSeattleUSA

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