6d48271c-5ac8-41f0-8afc-f1954936243a
SUMO and proteasome inhibition in multiple myeloma
Relapsed/refractory multiple myeloma (MM) is a disease with poor prognosis. Hyperactive SUMO signalling 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 relapsed/refractory MM is characterized by a SUMO-high state, and high expression of the SUMO E1 activating enzyme (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 inhibitor targeting the SUMO E1 activating enzyme, 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, combinatorial treatment of subasumstat and CFZ enhanced genotoxic and proteotoxic 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 and potent strategy for the treatment of patients with MM.
Relapsed/refractory multiple myeloma (MM) is a disease with poor prognosis. Hyperactive SUMO signalling 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 relapsed/refractory MM is characterized by a SUMO-high state, and high expression of the SUMO E1 activating enzyme (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 inhibitor targeting the SUMO E1 activating enzyme, 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, combinatorial treatment of subasumstat and CFZ enhanced genotoxic and proteotoxic 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 and potent strategy for the treatment of patients with MM.