PXD025808

PXD025808 is an original dataset announced via ProteomeXchange.

Title	CK1δ/CK1ε Signaling is Necessary to Sustain mitochondrial Metabolism and Cell Survival in Multiple Myeloma
Description	Multiple myeloma (MM) remains an incurable malignancy due to the acquisition of intrinsic programs that drive therapy resistance. Here we report that casein kinase-1δ (CK1δ) and CK1ε are therapeutic targets for MM that control mitochondrial metabolism. Specifically, SR-3029, a dual CK1δ/CK1ε inhibitor, has potent anti-MM activity in vivo and ex vivo (in 74/75 patient specimens). Mechanistically, RNA sequencing (RNA-seq) and metabolic analyses revealed that inhibiting CK1δ/CK1ε disables MM metabolism, by suppressing genes involved in oxidative phosphorylation (OxPhos), reducing citric acid cycle intermediates, and suppressing Complexes I and IV of the electron transport chain. Finally, sensitivity of MM patient specimens to SR-3029 correlates with elevated expression of mitochondrial genes, and RNA-seq of tumor cells from 687 MM patients spanning the spectrum from newly diagnosed to late relapsed refractory disease revealed increased CSNK1D, CSNK1E, and OxPhos genes correlate with disease progression and inferior outcomes. Thus, increases in mitochondrial metabolism are a hallmark of MM progression that can be disabled by targeting CK1δ/CK1ε.
HostingRepository	PRIDE
AnnounceDate	2024-01-26
AnnouncementXML	Submission_2024-01-26_06:45:56.946.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD025808
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	biotinylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-05-05 08:59:30	ID requested
⏵ 1	2024-01-26 06:45:58	announced

10.6019/PXD025808;

10.1158/0008-5472.can-22-2350;

Burger KL, Fernandez MR, Meads MB, Sudalagunta P, Oliveira PS, Renatino Canevarolo R, Alugubelli RR, Tungsevik A, De Avila G, Silva M, Graeter AI, Dai HA, Vincelette ND, Prabhu A, Magaletti D, Yang C, Li W, Kulkarni A, Hampton O, Koomen JM, Roush WR, Monastyrskyi A, Berglund AE, Silva AS, Cleveland JL, Shain KH, Signaling Sustains Mitochondrial Metabolism and Cell Survival in Multiple Myeloma. Cancer Res, 83(23):3901-3919(2023) [pubmed]

submitter keyword: mitochondrial metabolism,Multiple myeloma, casein kinase, activity-based protein profiling

Kenneth Shain, MD/PhD
contact affiliation	Tumor Biology & Malignant Hematology Moffitt Cancer Center Tampa, FL, USA
contact email	ken.shain@moffitt.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD025808
     1. Label: PRIDE project
     2. Name: CK1δ/CK1ε Signaling is Necessary to Sustain mitochondrial Metabolism and Cell Survival in Multiple Myeloma