An inhibitor of proteasome beta 2 sites sensitizes myeloma cells to immunoproteasome inhibitors

Proteasome inhibitors bortezomib, carfilzomib and ixazomib (approved by the US Food and Drug Administration [FDA]) induce remissions in patients with multiple myeloma (MM), but most patients eventually become resistant. MM and other hematologic malignancies express ubiquitous constitutive proteasomes and lymphoid tissue-specific immunoproteasomes; immunoproteasome expression is increased in resistant patients. Immunoproteasomes contain 3 distinct pairs of active sites, beta 5i, beta 1i, and beta 2i, which are different from their constitutive beta 5c, beta 1c, and beta 2c counterparts. Bortezomib and carfilzomib block beta 5c and beta 5i sites. We report here that pharmacologically relevant concentrations of beta 5i-specific inhibitor ONX-0914 show cytotoxicity in MM cell lines similar to that of carfilzomib and bortezomib. In addition, increasing immunoproteasome expression by interferon-gamma increases sensitivity to ONX-0914 but not to carfilzomib. LU-102, an inhibitor of beta 2 sites, dramatically sensitizes MM cell lines and primary cells to ONX-0914. ONX-0914 synergizes with all FDA-approved proteasome inhibitors in MM in vitro and in vivo. Thus, immunoproteasome inhibitors, currently in clinical trials for the treatment of autoimmune diseases, should also be considered for the treatment of MM.