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SUMOylation inhibition overcomes proteasome inhibitor resistance in multiple myeloma

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Item Type:Article
Title:SUMOylation inhibition overcomes proteasome inhibitor resistance in multiple myeloma
Creators Name:Heynen, G.J.J.E. and Baumgartner, F. and Heider, M. and Patra, U. and Holz, M. and Braune, J. and Kaiser, M. and Schäffer, I. and Bamopoulos, S.A. and Ramberger, E. and Murgai, A. and Ng, Y.L.D. and Demel, U.M. and Laue, D. and Liebig, S. and Krüger, J. and Janz, M. and Nogai, A. and Schick, M. and Mertins, P. and Müller, S. and Bassermann, F. and Krönke, J. and Keller, U. and Wirth, M.
Abstract:Proteasome inhibition is a highly effective treatment for multiple myeloma (MM). However, virtually all patients develop proteasome inhibitor resistance which is associated with a poor prognosis. Hyperactive SUMO signaling is involved in both cancer pathogenesis and cancer progression. A state of increased SUMOylation has been associated with aggressive cancer biology. We found that relapsed/refractory MM is characterized by a SUMO-high state, and high expression of the SUMO E1 activating enzyme (SAE1/UBA2) is associated with poor overall survival. Consistently, continuous treatment of MM cell lines with carfilzomib (CFZ) enhanced SUMO pathway activity. Treatment of MM cell lines with the SUMO E1 activating enzyme inhibitor subasumstat (TAK-981) showed synergy with CFZ in both CFZ-sensitive and CFZ-resistant MM cell lines, irrespective of the TP53 state. Combination therapy was effective in primary MM cells and in two murine MM xenograft models. Mechanistically, combination treatment with subasumstat and CFZ enhanced genotoxic and proteotoxic stress and induced apoptosis was associated with activity of the prolyl isomerase PIN1. In summary, our findings reveal activated SUMOylation as a therapeutic target in MM and point to combined SUMO/proteasome inhibition as a novel and potent strategy for the treatment of proteasome inhibitor-resistant MM.
Keywords:Apoptosis, Multiple Myeloma, NIMA-Interacting Peptidylprolyl Isomerase, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Sumoylation, Ubiquitin-Activating Enzymes, Animals, Mice
Source:Blood Advances
Publisher:American Society of Hematology
Page Range:469-481
Date:28 February 2023
Official Publication:https://doi.org/10.1182/bloodadvances.2022007875
PubMed:View item in PubMed

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