An inhibitor of proteasome b2 sites sensitizes myeloma cells to immunoproteasome inhibitors

Abstract

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. Immunoprotea-somes contain 3 distinct pairs of active sites, b5i, b1i, and b2i, which are different from their constitutive b5c, b1c, and b2c counterparts. Bortezomib and carfilzomib block b5c and b5i sites. We report here that pharmacologically relevant concentrations of b5i-specific inhibitor ONX-0914 show cytotoxicity in MM cell lines similar to that of carfilzomib and bortezomib. In addition, increasing immunoproteasome expression by interferon-g increases sensitivity to ONX-0914 but not to carfilzomib. LU-102, an inhibitor of b2 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.