PXD042728-1

PXD042728 is an original dataset announced via ProteomeXchange.

Title	Disruption of the ALK tumor cell proteome by concurrent inhibation of ALK and SRC kinases
Description	Precision oncology has revolutionized the treatment of ALK-positive lung cancer with targeted therapies. However, refractory tumors with compound mutations or diverse resistance mechanisms remain an unmet clinical need. In this study, we established mouse tumor-derived cell models representing the most common EML4-ALK variants in human lung adenocarcinomas and characterized their proteomic profiles. We demonstrated that Eml4-Alk variant 3 confers a worse response to ALK inhibitors, suggesting its role in promoting resistance. In addition, proteomic analysis of brigatinib-treated cells revealed the upregulation of SRC kinase, which is frequently activated in cancer. Co-targeting of ALK and SRC showed remarkable inhibitory effects on both ALK-driven murine tumor growth and ALK-patient-derived cells. This death mechanism is attributed to the profound perturbation of the (phospho)proteomic landscape, together with a synergistic suppressive effect on the mTOR pathway. Taken together, our study identifies the inhibition of ALK and SRC cells and may offer a promising strategy to overcome resistance mechanisms and improve clinical outcomes in ALK-positive lung cancer patients.
HostingRepository	PRIDE
AnnounceDate	2024-04-11
AnnouncementXML	Submission_2024-04-11_00:17:42.763.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marcel Schilling
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-06-05 06:25:22	ID requested
⏵ 1	2024-04-11 00:17:43	announced
2	2024-10-22 06:35:49	announced	2024-10-22: Updated project metadata.

10.1016/j.drup.2024.101081;

Diaz-Jimenez A, Ramos M, Helm B, Chocarro S, Frey DL, Agrawal S, Somogyi K, Klingm, ü, ller U, Lu J, Sotillo R, Concurrent inhibition of ALK and SRC kinases disrupts the ALK lung tumor cell proteome. Drug Resist Updat, 74():101081(2024) [pubmed]

submitter keyword: (phospho)proteomics, EML4-ALK,Precision oncology, tyrosine kinase inhibitor (TKIs), non-small cell lung cancer (NSCLC)

Prof. Ursula Klingmüller
contact affiliation	German Cancer Research Center Heidelberg, Division: Systems Biology of Singal Transduction
contact email	u.klingmueller@dkfz.de
lab head
Marcel Schilling
contact affiliation	Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg
contact email	m.schilling@dkfz.de
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/2024/04/PXD042728

PRIDE project URI

• PRIDE
  1. PXD042728
     1. Label: PRIDE project
     2. Name: Disruption of the ALK tumor cell proteome by concurrent inhibation of ALK and SRC kinases