PXD018744-2

PXD018744 is an original dataset announced via ProteomeXchange.

Title	Multilayered proteomics uncovers Notch/PKC targeting to overcome resistance to Notch inhibition in acute lymphoblastic leukemia
Description	NOTCH1 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.
HostingRepository	PRIDE
AnnounceDate	2021-03-08
AnnouncementXML	Submission_2021-05-28_01:05:24.780.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	Q Exactive HF; Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2020-04-22 23:35:08	ID requested
1	2021-03-08 08:07:58	announced
⏵ 2	2021-05-28 01:05:25	announced	2021-05-28: Updated publication reference for PubMed record(s): 33947863.
3	2022-02-14 02:01:12	announced	2022-02-14: Updated project metadata.

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]

submitter keyword: Notch signaling, PKCδ, proteomics, drug resistance, T-ALL

Jesper Velgaard Olsen
contact affiliation	Novo Nordisk Foundation Center for Protein Research Proteomics Program University of Copenhagen Faculty of Health and Medical Sciences Blegdamsvej 3b DK-2200 Copenhagen Denmark
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

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/2021/03/PXD018744

PRIDE project URI

• PRIDE
  1. PXD018744
     1. Label: PRIDE project
     2. Name: Multilayered proteomics uncovers Notch/PKC targeting to overcome resistance to Notch inhibition in acute lymphoblastic leukemia