PXD030338

PXD030338 is an original dataset announced via ProteomeXchange.

Title	Tyr62 phosphorylation of the phosphatase SHP2 enables acquired resistance to SHP2 allosteric inhibitors in FLT3-ITD-driven AML
Description	The protein tyrosine phosphatase SHP2 is crucial for oncogenic transformation of acute myeloid leukemia (AML) cells expressing mutated receptor tyrosine kinases (RTKs), as it is required for full RAS-ERK activation to promote cell proliferation and survival programs. SHP2 allosteric inhibitors act by stabilizing SHP2 in its auto-inhibited conformation and they are currently being tested in clinical trials for tumors with over-activation of the RAS/ERK pathway, alone and in various drug combinations. Using in vitro models, we established acquired resistant cell lines to the allosteric SHP2 inhibitor SHP099 from two FLT3-ITD-positive AML cell lines. We performed both label-free and isobaric labeling quantitative mass spectrometry-based phosphoproteomics to reveal that AML cells can restore phosphorylated ERK (pERK) in presence of SHP099, thus developing adaptive resistance. Mechanistically, SHP2 inhibition induces the tyrosine phosphorylation and feedback-activation of the FLT3 receptor, which in turn phosphorylates SHP2 on Tyrosine 62. This phosphorylation stabilizes SHP2 in its open conformation, preventing SHP099 binding, thus resulting in resistance. Combinatorial inhibition of SHP2 and MEK or SHP2 and FLT3 prevents pERK rebound and resistant cell growth. We observed the same mechanism in a FLT3-mutated B-ALL cell line and in the inv(16)/KITD816Y AML mouse model. Finally, we show that allosteric SHP2 inhibition does not impair the clonogenic ability of normal bone marrow progenitors, supporting its future use for clinical applications.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:40:52.358.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Giulia Franciosa
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Exploris 480; Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-12 14:17:52	ID requested
1	2023-03-11 02:37:34	announced
⏵ 2	2023-11-14 08:40:55	announced	2023-11-14: Updated project metadata.

Pfeiffer A, Franciosa G, Locard-Paulet M, Piga I, Reckzeh K, Vemulapalli V, Blacklow SC, Theilgaard-M, ö, nch K, Jensen LJ, Olsen JV, Phosphorylation of SHP2 at Tyr62 Enables Acquired Resistance to SHP2 Allosteric Inhibitors in FLT3-ITD-Driven AML. Cancer Res, 82(11):2141-2155(2022) [pubmed]

submitter keyword: SHP2, PTPN11, proteomics, drug resistance, AML

Jesper Velgaard Olsen
contact affiliation	Novo Nordisk Foundation Center for Protein Research University of Copenhagen Faculty of Health and Medical Sciences Blegdamsvej 3B København N
contact email	jesper.olsen@cpr.ku.dk
lab head
Giulia Franciosa
contact affiliation	Novo Nordisk Foundation Center For Protein Research, Copenhagen University, Copenhagen
contact email	giulia.franciosa@cpr.ku.dk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD030338
     1. Label: PRIDE project
     2. Name: Tyr62 phosphorylation of the phosphatase SHP2 enables acquired resistance to SHP2 allosteric inhibitors in FLT3-ITD-driven AML