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Bortezomib sensitivity is tissue dependent and high expression of the 20S proteasome precludes good response in malignant pleural mesothelioma

Authors Walter RFH, Sydow SR, Berg E, Kollmeier J, Christoph DC, Christoph S, Eberhardt WEE, Mairinger T, Wohlschlaeger J, Schmid KW, Mairinger FD

Received 12 November 2018

Accepted for publication 22 July 2019

Published 24 September 2019 Volume 2019:11 Pages 8711—8720


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Dr Rituraj Purohit

Robert Fred Henry Walter,1,2 Saskia Roxanne Sydow,3 Erika Berg,3 Jens Kollmeier,4 Daniel Christian Christoph,5,6 Sandra Christoph,7 Wilfried Ernst Erich Eberhardt,1 Thomas Mairinger,4 Jeremias Wohlschlaeger,2 Kurt Werner Schmid,2 Fabian Dominik Mairinger2

1Ruhrlandklinik, West German Lung Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 2Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 3Institute of Pathology, Charité Universitaetsmedizin, Berlin, Germany; 4Institute of Pathology, Helios Klinikum Emil Von Behring, Berlin, Germany; 5Department of Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 6Department of Internistic Oncology, Kliniken Essen Mitte, Essen, Germany; 7Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Correspondence: Robert Fred Henry Walter
University Hospital Essenm, Institute of Pathology, Hufelandstraße 55, Essen D-45147, Germany
Tel +49 0 201/723 84828
Fax +49 0 201/723 3880

Background: Bortezomib is an approved proteasome inhibitor for the treatment of certain lymphoma subtypes. Two clinical trials investigated bortezomib in patients with malignant pleural mesothelioma (MPM) and failed to improve outcome. We present a potential explanation for this event.
Methods: 171 patients with MPM were analyzed for their mRNA expression of proteasomal subunits PSMA1, PSMA5, PSMB1, PSMB2, PSMB4 and PSMB5 via qPCR (n=84) or sequencing (n=87 TCGA/cBioPortal data set “Mesothelioma”). Outcome and subunit expression were correlated. Four mesothelial and one fibroblast cell line were treated with bortezomib and cisplatin. Cellular response was measured after 0, 6, 12, 24, 48 and 72 hrs. Enzyme activity of proteasomal subunits was assessed via functional enzyme activity assays.
Results: Patients with MPM presented with elevated expression of proteasomal subunits compared to benign controls (p<0.001). PSMB4 correlated with outcome (Cox propotiortional-hazards model (COXPH): p<0.0175, TCGA/cBioPortal data). In cell lines, apoptosis was the main event with a peak after 48 hr incubation for bortezomib or cisplatin. Only two cell lines with comparably low proteasome activity (PSMB2 and PSMB5) responded to 50 nM and 100 nM bortezomib better than to cisplatin (MRC-5, NCI-H2052). MSTO-211H responded to cisplatin only, whereas the other two cell lines were considered therapy resistant (Met-5A, NCI-H2452).
Interpretation: Two clinical trials testing bortezomib in MPM failed, although MPM presents with high proteasome expression, which predicts bortezomib sensitivity in several tumors. Bortezomib induced apoptosis in MPM cell lines with low proteasome activity only. Bortezomib is not suitable for the treatment of MPM, and biomarker-based stratification could have improved both clinical trials.
Trial registration: NCT00513877 and NCT00458913

Keywords: bortezomib, proteasome, malignant pleural mesothelioma, TCGA, biomarker

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