biostudies-literatureUnknown7(4)Heynen GJJEProteasome 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 syneBlood advances469-481https://www.ebi.ac.uk/biostudies/studies/S-EPMC9979771biostudies-literatureSUMOylation inhibition overcomes proteasome inhibitor resistance in multiple myeloma.PMC9979771Janz MKronke JNogai AWirth MMuller SHolz MMurgai AHeider MHeynen GJJEKaiser MNg YLDDemel UMBamopoulos SAKeller USchaffer IRamberger EKruger JBassermann FLaue DPatra UBraune JMertins PLiebig SBaumgartner FSchick MfalseSUMOylation 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 syne2023-01-01T00:00:00Z2023 Feb2026-05-28T18:37:34.498Z2025-02-19T04:55:03.923ZS-EPMC99797713591756810.1182/bloodadvances.2022007875