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Experimental Hematology & Oncology
Published in: Experimental Hematology & Oncology 1/2013

Open Access 01-12-2013 | Research

Overcoming bortezomib resistance in human B cells by anti-CD20/rituximab-mediated complement-dependent cytotoxicity and epoxyketone-based irreversible proteasome inhibitors

Authors: Sue Ellen Verbrugge, Marjon Al, Yehuda G Assaraf, Denise Niewerth, Johan van Meerloo, Jacqueline Cloos, Michael van der Veer, George L Scheffer, Godefridus J Peters, Elena T Chan, Janet L Anderl, Christopher J Kirk, Sonja Zweegman, Ben AC Dijkmans, Willem F Lems, Rik J Scheper, Tanja D de Gruijl, Gerrit Jansen

Published in: Experimental Hematology & Oncology | Issue 1/2013

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Abstract

Background

In clinical and experimental settings, antibody-based anti-CD20/rituximab and small molecule proteasome inhibitor (PI) bortezomib (BTZ) treatment proved effective modalities for B cell depletion in lymphoproliferative disorders as well as autoimmune diseases. However, the chronic nature of these diseases requires either prolonged or re-treatment, often with acquired resistance as a consequence.

Methods

Here we studied the molecular basis of acquired resistance to BTZ in JY human B lymphoblastic cells following prolonged exposure to this drug and examined possibilities to overcome resistance by next generation PIs and anti-CD20/rituximab-mediated complement-dependent cytotoxicity (CDC).

Results

Characterization of BTZ-resistant JY/BTZ cells compared to parental JY/WT cells revealed the following features: (a) 10–12 fold resistance to BTZ associated with the acquisition of a mutation in the PSMB5 gene (encoding the constitutive β5 proteasome subunit) introducing an amino acid substitution (Met45Ile) in the BTZ-binding pocket, (b) a significant 2–4 fold increase in the mRNA and protein levels of the constitutive β5 proteasome subunit along with unaltered immunoproteasome expression, (c) full sensitivity to the irreversible epoxyketone-based PIs carfilzomib and (to a lesser extent) the immunoproteasome inhibitor ONX 0914. Finally, in association with impaired ubiquitination and attenuated breakdown of CD20, JY/BTZ cells harbored a net 3-fold increase in CD20 cell surface expression, which was functionally implicated in conferring a significantly increased anti-CD20/rituximab-mediated CDC.

Conclusions

These results demonstrate that acquired resistance to BTZ in B cells can be overcome by next generation PIs and by anti-CD20/rituximab-induced CDC, thereby paving the way for salvage therapy in BTZ-resistant disease.
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Metadata
Title
Overcoming bortezomib resistance in human B cells by anti-CD20/rituximab-mediated complement-dependent cytotoxicity and epoxyketone-based irreversible proteasome inhibitors
Authors
Sue Ellen Verbrugge
Marjon Al
Yehuda G Assaraf
Denise Niewerth
Johan van Meerloo
Jacqueline Cloos
Michael van der Veer
George L Scheffer
Godefridus J Peters
Elena T Chan
Janet L Anderl
Christopher J Kirk
Sonja Zweegman
Ben AC Dijkmans
Willem F Lems
Rik J Scheper
Tanja D de Gruijl
Gerrit Jansen
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Experimental Hematology & Oncology / Issue 1/2013
Electronic ISSN: 2162-3619
DOI
https://doi.org/10.1186/2162-3619-2-2

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