PXD001680

PXD001680 is an original dataset announced via ProteomeXchange.

Title	A common cell state in Triple Negative Breast Cancers can be targeted through inhibition of Spleen Tyrosine Kinase (SYK)
Description	Breast tumors are highly heterogeneous and for many molecular subtypes no targeted therapies are available. These include breast cancers that display hallmarks of epithelial to mesenchymal transition (EMT), a process related to metastasis and enriched in triple negative breast cancers (TNBCs). To determine whether this EMT cellular state could be therapeutically exploited, we performed a large-scale chemical genetic screen. We identified a group of structurally related compounds, including the clinically advanced drug PKC412 (midostaurin), that targeted post-EMT breast cancer cells. PKC412 induced apoptosis specifically in basal-like TNBC cells and inhibited tumor growth in vivo. Structure activity relationship (SAR) studies, chemical proteomics, and computational modeling identified the kinase SYK as a critical PKC412 target. Specific SYK inhibitors and PKC412 displayed a similar profile across a large panel of breast cancer cell lines, indicating a shared mode of action. Phosphoproteomics analysis revealed that SYK activates STAT3, and chemical or genetic inhibition of STAT3 resulted in cell death in basal-like breast cancer cells. This non-oncogene addiction of basal-like breast cancer cells to SYK suggests that chemical SYK inhibition may be beneficial for a specific subset of triple negative breast cancer patients.
HostingRepository	PRIDE
AnnounceDate	2016-06-15
AnnouncementXML	Submission_2016-06-15_08:07:39.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Andre Mueller
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2015-01-14 08:33:10	ID requested
⏵ 1	2016-06-15 08:07:40	announced

Muellner MK, Mair B, Ibrahim Y, Kerzendorfer C, Lechtermann H, Trefzer C, Klepsch F, M, ü, ller AC, Leitner E, Macho-Maschler S, Superti-Furga G, Bennett KL, Baselga J, Rix U, Kubicek S, Colinge J, Serra V, Nijman SM, Targeting a cell state common to triple-negative breast cancers. Mol Syst Biol, 11(1):789(2015) [pubmed]

curator keyword: Biomedical

submitter keyword: Human breast cancer, SYK inhibition, phosphotyrosine proteomics

Keiryn L. Bennett
contact affiliation	CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT 25.3 1090 Vienna, Austria
contact email	kbennett@cemm.oeaw.ac.at
lab head
Andre Mueller
contact affiliation	Research Center for Molecular Medicine of the Austrian Academy of Sciences
contact email	amueller@cemm.oeaw.ac.at
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/2016/06/PXD001680

PRIDE project URI

• PRIDE
  1. PXD001680
     1. Label: PRIDE project
     2. Name: A common cell state in Triple Negative Breast Cancers can be targeted through inhibition of Spleen Tyrosine Kinase (SYK)