PXD004442

PXD004442 is an original dataset announced via ProteomeXchange.

Title	Phosphoproteome Analysis Reveals Differential Mode of Action of Sorafenib in Wildtype and Mutated FLT3 AML Cells
Description	Constitutively activating internal tandem duplication (ITD) alterations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) are common in acute myeloid leukemia (AML) and classifies FLT3 as an attractive therapeutic target. So far, application of FLT3 small molecule inhibitors such as Sorafenib has resulted only in partial and transient clinical responses in FLT3-ITD+ patients. Only recently, a prolonged event-free survival has been observed in AML patients who were treated with Sorafenib in addition to standard therapy. Here, we studied the Sorafenib effect on proliferation in a panel of 13 FLT3-ITD- and FLT3-ITD+ AML cell lines. Sorafenib IC50 values ranged from 0.001 to 5.6 µM, whereas FLT3-ITD+ cells (MOLM-13, MV4;11) were found more sensitive to Sorafenib than FLT3-ITD- cells. However, we identified two FLT3-ITD- cell lines (MONO-MAC-1 and OCI-AML-2) which were also Sorafenib sensitive. Phosphoproteome analyses revealed that the affected pathways differed in Sorafenib sensitive FLT3-ITD- and FLT3-ITD+ cells. In MV4;11 cells Sorafenib suppressed mTOR signalling by inhibiting direct inhibition of FLT3. In MONO-MAC-1 cells Sorafenib inhibited the MEK/ERK pathway by inhibition of the RET tyrosine kinase. These data suggest that the FLT3 status in AML patients might not be the only predictive factor for a response to Sorafenib.
HostingRepository	PRIDE
AnnounceDate	2017-05-02
AnnouncementXML	Submission_2017-05-02_05:08:03.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christoph Schaab
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2016-06-27 01:35:13	ID requested
⏵ 1	2017-05-02 05:08:05	announced

Roolf C, Dybowski N, Sekora A, Mueller S, Knuebel G, Tebbe A, Murua Escobar H, Godl K, Junghanss C, Schaab C, Phosphoproteome Analysis Reveals Differential Mode of Action of Sorafenib in Wildtype and Mutated FLT3 Acute Myeloid Leukemia (AML) Cells. Mol Cell Proteomics, 16(7):1365-1376(2017) [pubmed]

curator keyword: Biomedical

submitter keyword: Acute myeloid Leukemia, FLT3, Phosphoproteomics, Sorafenib

Christoph Schaab
contact affiliation	Evotec (München) GmbH, Martinsried, Germany
contact email	christoph.schaab@evotec.com
lab head
Christoph Schaab
contact affiliation	Evotec
contact email	christoph.schaab@evotec.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD004442
     1. Label: PRIDE project
     2. Name: Phosphoproteome Analysis Reveals Differential Mode of Action of Sorafenib in Wildtype and Mutated FLT3 AML Cells