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PXD032030-1

PXD032030 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleAllosteric HSP70 inhibitors in Proteasome Inhibitor Resistant Multiple Myeloma
DescriptionProteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first mapped proteasome-associated genetic co-dependencies. We identified cytosolic heat shock protein 70 (HSP70) chaperones as potential targets, consistent with proposed mechanisms of myeloma tumor cells overcoming PI-induced stress. These results led us to explore allosteric HSP70 inhibitors (JG compounds) as myeloma therapeutics. We showed these compounds exhibit increased efficacy against acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Surprisingly, shotgun and pulsed-SILAC mass spectrometry found that JGs have the most pronounced effect on the proteome not through inhibiting cytosolic HSP70s but instead through mitochondrial-localized HSP70, HSPA9/mortalin, destabilizing the 55S mitoribosome. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize myeloma proteostasis networks under therapeutic pressure while motivating further investigation of HSPA9 as a specific vulnerability in PI-resistant disease.
HostingRepositoryPRIDE
AnnounceDate2022-05-27
AnnouncementXMLSubmission_2022-05-26_19:30:08.789.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterIan Ferguson
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListiodoacetamide derivatized residue
InstrumentQ Exactive Plus
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-03-03 11:27:56ID requested
12022-05-26 19:30:09announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: Proteasome Inhibitor, Multiple Myeloma, HSP70
Contact List
Arun Wiita
contact affiliationDept. of Laboratory Medicine, University of California, San Francisco
contact emailarun.wiita@ucsf.edu
lab head
Ian Ferguson
contact affiliationStanford University
contact emailifergus@stanford.edu
dataset submitter
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Dataset FTP location
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