PXD032030-1

PXD032030 is an original dataset announced via ProteomeXchange.

Title	Allosteric HSP70 inhibitors in Proteasome Inhibitor Resistant Multiple Myeloma
Description	Proteasome 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.
HostingRepository	PRIDE
AnnounceDate	2022-05-27
AnnouncementXML	Submission_2022-05-26_19:30:08.789.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ian Ferguson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-03 11:27:56	ID requested
⏵ 1	2022-05-26 19:30:09	announced

Dataset with its publication pending

submitter keyword: Proteasome Inhibitor, Multiple Myeloma, HSP70

Arun Wiita
contact affiliation	Dept. of Laboratory Medicine, University of California, San Francisco
contact email	arun.wiita@ucsf.edu
lab head
Ian Ferguson
contact affiliation	Stanford University
contact email	ifergus@stanford.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD032030
     1. Label: PRIDE project
     2. Name: Allosteric HSP70 inhibitors in Proteasome Inhibitor Resistant Multiple Myeloma