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PXD018744-2

PXD018744 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleMultilayered proteomics uncovers Notch/PKC targeting to overcome resistance to Notch inhibition in acute lymphoblastic leukemia
DescriptionNOTCH1 is a crucial oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL), making it an attractive therapeutic target. However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to toxicity and development of resistance, thus restricting their clinical efficacy. Here we systematically compare GSI resistant and sensitive cell states by quantitative mass spectrometry-based phosphoproteomics, using complementary models of resistance, including T-ALL patient-derived xenografts (PDX) models. Our datasets reveal common mechanisms of GSI resistance, including a distinct kinase signature that involves protein kinase C delta (PKCδ). We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance “in-vitro”. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.
HostingRepositoryPRIDE
AnnounceDate2021-03-08
AnnouncementXMLSubmission_2021-05-28_01:05:24.780.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterGiulia Franciosa
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue
InstrumentQ Exactive HF; Orbitrap Exploris 480
Dataset History
RevisionDatetimeStatusChangeLog Entry
02020-04-22 23:35:08ID requested
12021-03-08 08:07:58announced
22021-05-28 01:05:25announced2021-05-28: Updated publication reference for PubMed record(s): 33947863.
32022-02-14 02:01:12announced2022-02-14: Updated project metadata.
Publication List
Franciosa G, Smits JGA, Minuzzo S, Martinez-Val A, Indraccolo S, Olsen JV, Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures. Nat Commun, 12(1):2507(2021) [pubmed]
Keyword List
submitter keyword: Notch signaling, PKCδ, proteomics, drug resistance, T-ALL
Contact List
Jesper Velgaard Olsen
contact affiliationNovo Nordisk Foundation Center for Protein Research Proteomics Program University of Copenhagen Faculty of Health and Medical Sciences Blegdamsvej 3b DK-2200 Copenhagen Denmark
contact emailjesper.olsen@cpr.ku.dk
lab head
Giulia Franciosa
contact affiliationNovo Nordisk Foundation Center For Protein Research, Copenhagen University, Copenhagen
contact emailgiulia.franciosa@cpr.ku.dk
dataset submitter
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Dataset FTP location
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