PXD010787

PXD010787 is an original dataset announced via ProteomeXchange.

Title	Project Name: Functional proteomics of midostaurin in lung cancer cells: Chemical Proteomics
Description	Lung cancer is associated with high prevalence and mortality, and despite significant successes with targeted drugs in genomically defined subsets of lung cancer and immunotherapy, the majority of patients currently does not benefit from these therapies. Through a targeted drug screen, we found the recently approved multi-kinase inhibitor midostaurin to have potent activity in several lung cancer cells independent of its intended target, PKC, or a specific genomic marker. To determine the underlying mechanism of action we applied a layered functional proteomics approach and a new data integration method. Using chemical proteomics, we identified multiple midostaurin kinase targets in these cells. Network-based integration of these targets with quantitative tyrosine and global phosphoproteomics data using protein-protein interactions from the STRING database suggested multiple targets are relevant for the mode of action of midostaurin. Subsequent functional validation using RNA interference and selective small molecule probes showed that simultaneous inhibition of TBK1, PDK1 and AURKA was required to elicit midostaurin’s cellular effects. Immunoblot analysis of downstream signaling nodes showed that combined inhibition of these targets altered PI3K/AKT and cell cycle signaling pathways that in part converged on PLK1. Furthermore, rational combination of midostaurin with the more potent PLK1 inhibitor BI2536, which is in advanced clinical trials, elicited strong synergy. Our results demonstrate that combination of complementary functional proteomics approaches and subsequent network-based data integration can reveal novel insight into the complex mode of action of multi-kinase inhibitors, actionable targets for drug discovery and cancer vulnerabilities. Finally, we illustrate how this knowledge can be utilized for the rational design of synergistic drug combinations with high potential for clinical translation.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:48:13.040.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD010787
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Oxidation; Carbamidomethyl
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2018-08-15 03:56:49	ID requested
1	2018-09-24 01:59:57	announced
2	2018-12-04 04:00:27	announced	Updated project metadata.
⏵ 3	2024-10-22 04:48:13	announced	2024-10-22: Updated project metadata.

Ctortecka C, Palve V, Kuenzi BM, Fang B, Sumi NJ, Izumi V, Novakova S, Kinose F, Remsing Rix LL, Haura EB, Koomen JM, Rix U, Functional Proteomics and Deep Network Interrogation Reveal a Complex Mechanism of Action of Midostaurin in Lung Cancer Cells. Mol Cell Proteomics, 17(12):2434-2447(2018) [pubmed]

10.6019/PXD010787;

10.1074/mcp.ra118.000713;

ProteomeXchange project tag: Cancer (B/D-HPP)

curator keyword: Biological

submitter keyword: Drug Pulldown,Midostaurin, Chemical Proteomics, Lung Cancer

Uwe Rix, PhD
contact affiliation	Moffitt Cancer Center Tampa, FL
contact email	uwe.rix@moffitt.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
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/2018/09/PXD010787

PRIDE project URI

• PRIDE
  1. PXD010787
     1. Label: PRIDE project
     2. Name: Project Name: Functional proteomics of midostaurin in lung cancer cells: Chemical Proteomics