PXD032316

PXD032316 is an original dataset announced via ProteomeXchange.

Title	Synergistic efficacy of combined SUMOylation and proteasome inhibition in multiple myeloma
Description	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.
HostingRepository	PRIDE
AnnounceDate	2022-08-01
AnnouncementXML	Submission_2022-08-01_05:23:53.233.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Evelyn Ramberger
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-16 04:11:38	ID requested
⏵ 1	2022-08-01 05:23:53	announced

Dataset with its publication pending

submitter keyword: SUMOylation inhibitor, myeloma, proteasome inhibitor

Philipp Mertins
contact affiliation	Proteomics Platform, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
contact email	Philipp.Mertins@mdc-berlin.de
lab head
Evelyn Ramberger
contact affiliation	Max Delbrück Center for Molecular Medicine, Berlin
contact email	evelyn.ramberger@mdc-berlin.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD032316
     1. Label: PRIDE project
     2. Name: Synergistic efficacy of combined SUMOylation and proteasome inhibition in multiple myeloma