Proteasome Inhibition in Multiple Myeloma: Head-to-Head Comparison of Currently Available Proteasome Inhibitors. Issue 3 (21st March 2019)

• Record Type: Journal Article
• Authors: Besse, Andrej; Besse, Lenka; Kraus, Marianne; Mendez-Lopez, Max; Bader, Jürgen; Xin, Bo-Tao; de Bruin, Gerjan; Maurits, Elmer; Overkleeft, Herman S.; Driessen, Christoph
• Is Part Of: Cell chemical biology. Volume 26:Issue 3(2019)
• Page Start: 340
• Page End: 351.e3
• Publication Date: 2019-03-21
• Subjects: multiple myeloma -- proteasome -- proteasome inhibitors -- bortezomib -- carfilzomib -- resistance -- activity-based probes; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2018.11.007
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Proteasome inhibitors (PIs) are a backbone of multiple myeloma (MM) therapy. The proteasome harbors six proteolytically active subunits (β1, β2, β5), while β5 was identified as rate-limiting and is a primary target of clinically available PIs. The most effective pattern of subunit inhibition provided by these PIs for cytotoxic activity in MM is unknown. A head-to-head comparison of clinically available PIs shows that in the clinically relevant setting only the co-inhibition of β1 or β2 with β5 activity achieves meaningful functional proteasome inhibition and cytotoxicity, while the selective β2/β5 inhibition of both constitutive and immunoproteasome is the most cytotoxic. In the long-term setting, selective inhibition of β5 subunit is sufficient to induce cytotoxicity in PI-sensitive, but not in PI-resistant MM, and the β5/β2 co-inhibition is the most cytotoxic in PI-resistant MM. These results give a rational basis for selecting individual PIs for the treatment of MM. Graphical Abstract: Highlights: Direct comparison of proteasome inhibitors by activity-based probes and Ub -G76V- GFP Short-term β5 inhibition alone is not cytotoxic for MM cells β5/β2 co-inhibition is the most effective in PI-sensitive and PI-resistant MM From the available PI, only high-dose carfilzomib provides β5/β2 co-inhibition Abstract : Besse et al. demonstrate that clinically available proteasome inhibitors designed to target β5 subunit are cytotoxic only when another proteasome subunit (β1 or β2) is co-inhibited. The co-inhibition of subunits is not equal and the most effective is β5 + β2 proteasome inhibition, effective also against proteasome inhibitor-resistant multiple myeloma.