Abstract 1329: SUMOylation inhibition overcomes dexamethasone resistance in multiple myeloma

Multiple myeloma (MM), the second most common hematopoietic cancer, remains incurable, as patients inevitably relapse after initially responding to therapy. Dexamethasone (Dex) is a corticosteroid which has been widely used to treat MM as single drug or combination with other drugs. However, intrinsic and acquired Dex resistance is broadly associated with poor prognosis in MM. Thus, there is a continuing demanding on revealing Dex resistance mechanism and developing new drugs to overcome the resistance. One potential mechanism by which Dex resistance may be regulated is SUMOylation, a post-translational modification characterized by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins. SUMO activating enzyme E1 (UBA2/SAE2) gene expression was significantly upregulated in MM and associated with poor prognosis. Stably or transiently knockdown of SAE2 significantly reduced MM cell proliferation in MM cell lines RPMI8226 and MM1S. TAK-981, a novel, selective small molecule inhibitor of SUMO E1 enzyme, is currently in Phase 1 trials. In primary MM cells isolated from relapsing patients, TAK-981 enhanced Dex activity compared to the single agents alone. In Dex-resistant MM cell line MM1R, addition of TAK-981 to Dex treatment significantly enhanced its cytotoxicity. Anti-MM in vivo effects of SUMOylation inhibition was evaluated using a murine xenograft model by subcutaneously injecting MM1R cells into NSG mice. TAK-981 treatment greatly suppressed tumor growth and further reduced tumor burden in combination with Dex. Analysis of UBA2 mRNA level and cell viability assay with Dex treatment in primary MM samples demonstrated high SAE2 expression showed a significant correlation with decreased sensitivity to Dex. All these data indicated SUMOylation was associated with Dex resistance and SUMOylation inhibition enhanced Dex sensitivity in MM. Glucocorticoid receptor (GR) expression has been reported as a major mechanism of Dex resistance in MM. We observed a dose-dependent GR mRNA increase upon TAK-981 treatment in primary MM samples. miR-130b, a micro RNA targeting GR 39UTR, was downregulated upon TAK-981 treatment and associated with a concomitant upregulation of GR mRNA in both primary samples and MM1S, MM1R cell lines. To identify novel miRNAs involved in Dex resistance mechanism, we conducted genome wide RNA and miRNA profiling in MM1S and MM1R cells with Dex, TAK-981 single or combination treatment. We identified miR-551b and miR-25 as novel miRs mediating Dex resistance and SUMOylation inhibition suppressed both miRs levels through regulation c-Myc protein stability. In conclusion, our results demonstrate that SUMOylation inhibition overcomes Dex resistance in MM through upregulating GR and downregulating miR-551b and miR-25. Our findings reveal SUMOylation as a novel mechanism of Dex resistance, presenting SUMO E1 inhibitor as a potent therapy in MM. Citation Format: Li Du, Wei Liu, Steven T. Rosen. SUMOylation inhibition overcomes dexamethasone resistance in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1329.