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Mechanisms of Resistance to Immunotoxins Containing Pseudomonas Exotoxin A in Cancer Therapy

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA
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Biomolecules 2020, 10(7), 979; https://doi.org/10.3390/biom10070979
Received: 5 June 2020 / Revised: 25 June 2020 / Accepted: 27 June 2020 / Published: 30 June 2020
(This article belongs to the Special Issue Immunotoxins: From Design to Clinical Application)
Immunotoxins are a class of targeted cancer therapeutics in which a toxin such as Pseudomonas exotoxin A (PE) is linked to an antibody or cytokine to direct the toxin to a target on cancer cells. While a variety of PE-based immunotoxins have been developed and a few have demonstrated promising clinical and preclinical results, cancer cells frequently have or develop resistance to these immunotoxins. This review presents our current understanding of the mechanism of action of PE-based immunotoxins and discusses cellular mechanisms of resistance that interfere with various steps of the pathway. These steps include binding of the immunotoxin to the target antigen, internalization, intracellular processing and trafficking to reach the cytosol, inhibition of protein synthesis through ADP-ribosylation of elongation factor 2 (EF2), and induction of apoptosis. Combination therapies that increase immunotoxin action and overcome specific mechanisms of resistance are also reviewed. View Full-Text
Keywords: immunotoxin; Pseudomonas exotoxin A; immunotoxin resistance; combination therapy immunotoxin; Pseudomonas exotoxin A; immunotoxin resistance; combination therapy
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Dieffenbach, M.; Pastan, I. Mechanisms of Resistance to Immunotoxins Containing Pseudomonas Exotoxin A in Cancer Therapy. Biomolecules 2020, 10, 979.

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