Mechanisms of Resistance to Immunotoxins Containing Pseudomonas Exotoxin A in Cancer Therapy
Open Access
- 30 June 2020
- journal article
- review article
- Published by MDPI AG in Biomolecules
- Vol. 10 (7), 979
- https://doi.org/10.3390/biom10070979
Abstract
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.This publication has 69 references indexed in Scilit:
- Phase I Trial of Anti-CD22 Recombinant Immunotoxin Moxetumomab Pasudotox (CAT-8015 or HA22) in Patients With Hairy Cell LeukemiaJournal of Clinical Oncology, 2012
- Immunotoxin resistance via reversible methylation of the DPH4 promoter is a unique survival strategyProceedings of the National Academy of Sciences of the United States of America, 2012
- Killing of Resistant Cancer Cells with Low Bak by a Combination of an Antimesothelin Immunotoxin and a TRAIL Receptor 2 Agonist AntibodyClinical Cancer Research, 2011
- Synergistic Anticancer Effects of the 9.2.27PE Immunotoxin and ABT-737 in MelanomaPLOS ONE, 2011
- Cytotoxic Activity of Immunotoxin SS1P Is Modulated by TACE-Dependent Mesothelin SheddingCancer Research, 2011
- A guide to taming a toxin – recombinant immunotoxins constructed from Pseudomonas exotoxin A for the treatment of cancerThe FEBS Journal, 2011
- Pseudomonas Exotoxin A-Mediated Apoptosis Is Bak Dependent and Preceded by the Degradation of Mcl-1Molecular and Cellular Biology, 2010
- A protease-resistant immunotoxin against CD22 with greatly increased activity against CLL and diminished animal toxicityBlood, 2009
- Immunotoxin and Taxol synergy results from a decrease in shed mesothelin levels in the extracellular space of tumorsProceedings of the National Academy of Sciences of the United States of America, 2007
- Degradation of Mcl-1 by β-TrCP Mediates Glycogen Synthase Kinase 3-Induced Tumor Suppression and ChemosensitizationMolecular and Cellular Biology, 2007