title: The novel β2-selective proteasome inhibitor LU-102 synergizes with bortezomib and carfilzomib to overcome proteasome inhibitor resistance of myeloma cells.
abstract: Proteasome inhibitor resistance is a challenge for myeloma therapy. Bortezomib targets the β5 and β1 activity, but not the β2 activity of the proteasome. Bortezomib-resistant myeloma cells down-regulate the activation status of the unfolded protein response, and up-regulate β2 proteasome activity. To improve proteasome inhibition in bortezomib-resistant myeloma and to achieve more efficient UPR activation, we have developed LU-102, a selective inhibitor of the β2 proteasome activity. LU-102 inhibited the β2 activity in intact myeloma cells at low micromolar concentrations without relevant co-inhibition of β1 and β5 proteasome subunits. In proteasome inhibitor-resistant myeloma cells, significantly more potent proteasome inhibition was achieved by bortezomib or carfilzomib in combination with LU-102, compared to bortezomib/carfilzomib alone, resulting in highly synergistic cytotoxic activity of the drug combination via endoplasmatic reticulum stress-induced apoptosis. Combining bortezomib/carfilzomib with LU-102 significantly prolonged proteasome inhibition and increased activation of the unfolded protein response and IRE1-a activity. IRE1-α has recently been shown to control myeloma cell differentiation and bortezomib sensitivity (Leung-Hagesteijn, Cancer Cell 24:3, 289-304). Thus, β2-selective proteasome inhibition by LU-102 in combination with bortezomib or carfilzomib results in synergistic proteasome inhibition, activation of the unfolded protein response, and cytotoxicity, and overcomes bortezomib/carfilzomib resistance in myeloma cells in vitro.
authors.affiliation: Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St.Gallen, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Kraus
authors.affiliation: Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St.Gallen, Switzerland.
authors.forename: Juergen
authors.initials: J
authors.lastname: Bader
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, the Netherlands.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Geurink
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Weyburne
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Mirabella
authors.affiliation: Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St.Gallen, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Silzle
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
authors.forename: Tamer B
authors.initials: TB
authors.lastname: Shabaneh
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, the Netherlands.
authors.forename: Wouter A
authors.initials: WA
authors.lastname: van der Linden
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, the Netherlands.
authors.forename: Gerjan
authors.initials: G
authors.lastname: de Bruin
authors.affiliation: Clinical Trials Unit, Kantonsspital St. Gallen, Switzerland Department of Hematology, Division of Biostatistics, Institute for Social and Preventive Medicine, University of Zurich, Switzerland.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Haile
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: van Rooden
authors.affiliation: Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St.Gallen, Switzerland.
authors.forename: Christina
authors.initials: C
authors.lastname: Appenzeller
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, the Netherlands.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
authors.forename: Alexei F
authors.initials: AF
authors.lastname: Kisselev
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, the Netherlands.
authors.forename: Herman
authors.initials: H
authors.lastname: Overkleeft
authors.affiliation: Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St.Gallen, Switzerland Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, the Netherlands christoph.driessen@kssg.ch.
authors.forename: Christoph
authors.initials: C
authors.lastname: Driessen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C000602005:azido-Phe-Leu-Leu-4-aminomethyl-Phe-methyl vinyl sulfone; D000069286:Bortezomib; C524865:carfilzomib