PXD010217-1

PXD010217 is an original dataset announced via ProteomeXchange.

Title	Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia
Description	GSK3alpha 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.
HostingRepository	PRIDE
AnnounceDate	2019-01-29
AnnouncementXML	Submission_2019-01-29_06:03:46.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD010217
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	Oxidation; Carbamidomethyl
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2018-06-25 05:52:09	ID requested
⏵ 1	2019-01-29 06:03:48	announced
2	2024-10-22 04:46:15	announced	2024-10-22: Updated project metadata.

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]

curator keyword: Biomedical

submitter keyword: AML, Drug Pulldowns, Tivantinib

Uwe Rix, PhD
contact affiliation	Moffitt Cancer Center
contact email	uwe.rix@moffitt.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2019/01/PXD010217

PRIDE project URI

• PRIDE
  1. PXD010217
     1. Label: PRIDE project
     2. Name: Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia