• Marianne Kraus, Juergen Bader, Paul P Geurink, Emily S Weyburne, Anne C Mirabella, Tobias Silzle, Tamer B Shabaneh, Wouter A van der Linden, Gerjan de Bruin, Sarah R Haile, Eva van Rooden, Christina Appenzeller, Nan Li, Alexei F Kisselev, Herman Overkleeft, and Christoph Driessen.
• Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St.Gallen, Switzerland.
• Haematologica. 2015 Oct 1; 100 (10): 1350-60.

AbstractProteasome 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. Copyright© Ferrata Storti Foundation.

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