1. Bortezomib sensitivity is tissue dependent and high expression of the 20S proteasome precludes good response in malignant pleural mesothelioma
- Author
-
Walter RFH, Sydow SR, Berg E, Kollmeier J, Christoph DC, Christoph S, Eberhardt WEE, Mairinger T, Wohlschlaeger J, Schmid KW, and Mairinger FD
- Subjects
bortezomib ,proteasome ,malignant pleural mesothelioma ,TCGA ,biomarker ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
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, GermanyCorrespondence: Robert Fred Henry WalterUniversity Hospital Essenm, Institute of Pathology, Hufelandstraße 55, Essen D-45147, GermanyTel +49 0 201/723 84828Fax +49 0 201/723 3880Email robert.walter@ruhrlandklinik.uk-essen.deBackground: 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
- Published
- 2019