Synergistic efficacy of combined SUMOylation and proteasome inhibition in multiple myeloma

Relapsed/refractory multiple myeloma (r/r MM) is a disease with often 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. Here, we found that r/r MM is characterized by a SUMO-high state, and high expression of SUMO E1 ligase (SAE1/UBA2) was associated with poor overall survival. Induced resistance to the second generation proteasome inhibitor (PI) carfilzomib (CFZ) enhanced SUMO pathway activity. Accordingly, CFZ-pretreated patients showed enhanced SUMO pathway activity in the MM compartment. Treatment of MM cell lines with subasumstat, a novel small-molecule SUMO E1 activating enzyme inhibitor, showed synergistic treatment efficacy with CFZ in both PI-sensitive and PI-resistant MM cell lines irrespective of the TP53 state. Combination therapy was effective in two murine MM xenograft models, where in vivo growth was significantly inhibited, and in patient-derived primary MM cells in vitro. Mechanistically, combined subasumstat and CFZ treatment enhanced DNA stress and apoptosis. In summary, our findings reveal activated SUMOylation as a therapeutic target in MM and point to combined SUMO/proteasome inhibition as a novel potent strategy for the treatment of patients with MM.