PXD009996-1

PXD009996 is an original dataset announced via ProteomeXchange.

Title	Proteogenomic systems analysis identifies targeted therapy resistance mechanisms in EGFR-mutated lung cancer
Description	Cancer precision medicine largely relies on knowledge about genetic aberrations in tumors and next-generation-sequencing studies have shown a high mutational complexity in many cancers. Although a large number of the observed mutations is believed to be not causally linked with cancer, the functional effects of many rare mutations but also of combinations of driver mutations are often unknown. Here, we perform a systems analysis of a model of EGFR-mutated non-small cell lung cancer resistant to targeted therapy that integrates whole exome sequencing, global time-course discovery phosphoproteomics and computational modeling to identify functionally relevant molecular alterations. Our approach allows for a complexity reduction from over 2,000 genetic events potentially involved in mediating resistance to only 44 phosphoproteins and 35 topologically close genetic alterations. We perform single- and combination-drug testing against the predicted phosphoproteins and discovered that targeting of HSPB1, DBNL and AKT1 showed potent anti-proliferative effects overcoming resistance against EGFR-inhibitory therapy. Our approach may therefore be used to complement mutational profiling to identify functionally relevant molecular aberrations and propose combination therapies across cancers.
HostingRepository	PRIDE
AnnounceDate	2018-07-02
AnnouncementXML	Submission_2018-07-02_01:28:33.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Daniel Heim
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2018-06-01 01:52:52	ID requested
⏵ 1	2018-07-02 01:28:34	announced
2	2019-02-12 08:38:42	announced	Updated publication reference for PubMed record(s): 30183078.

Dataset with its publication pending

curator keyword: Biomedical

submitter keyword: Lung cancer, Proteomic, System Biology, Drug Resistance

Frederick Klauschen
contact affiliation	Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany.
contact email	frederick.klauschen@charite.de
lab head
Daniel Heim
contact affiliation	Charité Berlin
contact email	daniel.heim@charite.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/2018/07/PXD009996

PRIDE project URI

• PRIDE
  1. PXD009996
     1. Label: PRIDE project
     2. Name: Proteogenomic systems analysis identifies targeted therapy resistance mechanisms in EGFR-mutated lung cancer