Overcoming bortezomib resistance in human B cells by anti-CD20/rituximab-mediated complement-dependent cytotoxicity and epoxyketone-based irreversible proteasome inhibitors
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- 作者：Sue Ellen Verbrugge (1)
Marjon Al (1)
Yehuda G Assaraf (2)
Denise Niewerth (3)
Johan van Meerloo (3)
Jacqueline Cloos (3)
Michael van der Veer (4)
George L Scheffer (5)
Godefridus J Peters (4)
Elena T Chan (6)
Janet L Anderl (6)
Christopher J Kirk (6)
Sonja Zweegman (3)
Ben AC Dijkmans (1)
Willem F Lems (1)
Rik J Scheper (5)
Tanja D de Gruijl (4)
Gerrit Jansen (1) - 关键词：Proteasome inhibitors ; Anti ; CD20/rituximab therapy ; B cells ; Autoimmune disorders ; Resistance
- 刊名：Experimental Hematology & Oncology
- 出版年：2013
- 出版时间：December 2013
- 年：2013
- 卷：2
- 期：1
- 全文大小：446KB
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Marjon Al (1)
Yehuda G Assaraf (2)
Denise Niewerth (3)
Johan van Meerloo (3)
Jacqueline Cloos (3)
Michael van der Veer (4)
George L Scheffer (5)
Godefridus J Peters (4)
Elena T Chan (6)
Janet L Anderl (6)
Christopher J Kirk (6)
Sonja Zweegman (3)
Ben AC Dijkmans (1)
Willem F Lems (1)
Rik J Scheper (5)
Tanja D de Gruijl (4)
Gerrit Jansen (1)
1. Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands
2. The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, The Technion-Israel Institute of Technology, Haifa, Israel
3. Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands
4. Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
5. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
6. Onyx Pharmaceuticals, South San Francisco, CA, USA - ISSN：2162-3619
文摘
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) 10-2 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- 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.