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PXD010217

PXD010217 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleOff-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia
DescriptionGSK3alpha has been identified as a new target in the treatment of acute myeloid leukemia (AML). However, most GSK3 inhibitors lack specificity for GSK3alpha over GSK3beta and other kinases. We have previously shown in lung cancer cells that GSK3alpha and to a lesser extent GSK3beta are inhibited by the advanced clinical candidate tivantinib (ARQ197), which was designed as a MET inhibitor. Thus, we hypothesized that tivantinib would be an effective therapy for the treatment of AML. Here, we show that tivantinib has potent anticancer activity across several AML cell lines and primary patient cells. Tivantinib strongly induced apoptosis, differentiation and G2/M cell cycle arrest and caused less undesirable stabilization of beta-catenin compared to the pan-GSK3 inhibitor LiCl. Subsequent drug combination studies identified the BCL-2 inhibitor ABT-199 to synergize with tivantinib. Interestingly, the addition of ABT-199 to tivantinib completely abrogated tivantinib induced beta-catenin stabilization. Tivantinib alone, or in combination with ABT-199, downregulated anti-apoptotic MCL-1 and BCL-XL levels, which likely contribute to the observed synergy. Importantly, tivantinib as single agent or in combination with ABT-199 significantly inhibited the colony forming capacity of primary patient AML bone marrow mononuclear cells. In summary, tivantinib is a novel GSK3alpha/beta inhibitor that potently kills AML cells and tivantinib single agent or combination therapy with ABT-199 may represent attractive new therapeutic opportunities for AML.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_04:46:08.395.xml
DigitalObjectIdentifierhttps://dx.doi.org/10.6019/PXD010217
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterJohn Koomen
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListOxidation; Carbamidomethyl
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02018-06-25 05:52:09ID requested
12019-01-29 06:03:48announced
22024-10-22 04:46:15announced2024-10-22: Updated project metadata.
Publication List
10.6019/PXD010217;
10.1038/s41598-018-37174-6;
Kuenzi BM, Remsing Rix LL, Kinose F, Kroeger JL, Lancet JE, Padron E, Rix U, Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia. Sci Rep, 9(1):606(2019) [pubmed]
Keyword List
curator keyword: Biomedical
submitter keyword: AML, Tivantinib, Drug Pulldowns
Contact List
Uwe Rix, PhD
contact affiliationMoffitt Cancer Center
contact emailuwe.rix@moffitt.org
lab head
John Koomen
contact affiliationMoffitt Cancer Center
contact emailjohn.koomen@moffitt.org
dataset submitter
Full Dataset Link List
Dataset FTP location
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PRIDE project URI
Repository Record List
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