SUMOylation inhibition overcomes proteasome inhibitor resistance in multiple myeloma

Proteasome inhibition is a highly effective treatment for multiple myeloma (MM). However, virtually all patients develop proteasome inhibitor resistance, which is associated with a poor prognosis. Hyperactive small ubiquitin-like modifier (SUMO) signaling is involved in both cancer pathogenesis and cancer progression. A state of increased SUMOylation has been associated with aggressive cancer biology. We found that relapsed/refractory MM is characterized by a SUMO-high state, and high expression of the SUMO E1-activating enzyme (SAE1/UBA2) is associated with poor overall survival. Consistently, continuous treatment of MM cell lines with carfilzomib (CFZ) enhanced SUMO pathway activity. Treatment of MM cell lines with the SUMO E1-activating enzyme inhibitor subasumstat (TAK-981) showed synergy with CFZ in both CFZ-sensitive and CFZ-resistant MM cell lines, irrespective of the TP53 state. Combination therapy was effective in primary MM cells and in 2 murine MM xenograft models. Mechanistically, combination treatment with subasumstat and CFZ enhanced genotoxic and proteotoxic stress, and induced apoptosis was associated with activity of the prolyl isomerase PIN1. In summary, our findings reveal activated SUMOylation as a therapeutic target in MM and point to combined SUMO/proteasome inhibition as a novel and potent strategy for the treatment of proteasome inhibitor-resistant MM.

Automated summary

Proteasome inhibition is a highly effective treatment for multiple myeloma, but patients often develop resistance to proteasome inhibitors. Increased SUMOylation has been found in relapsed/refractory MM, and high expression of the SUMO E1-activating enzyme is associated with poor survival. Combination therapy with the SUMO E1-activating enzyme inhibitor and proteasome inhibitor showed synergy in MM cell lines and primary MM cells. Activated SUMOylation can be a therapeutic target for MM and combined SUMO/proteasome inhibition may be a potential strategy for treating proteasome inhibitor-resistant MM.