PXD004007

PXD004007 is an original dataset announced via ProteomeXchange.

Title	Phosphoproteome profiling reveals molecular mechanisms of growth factor mediated kinase inhibitor resistance in cancer cells
Description	Although substantial progress has been made regarding the use of molecularly targeted cancer therapies, resistance almost invariably develops and presents a major clinical challenge. To evade the selective pressure of kinase inhibitors, cells often activate bypass signaling tracks and become intrinsically resistant. Apart from intrinsic cellular adaptation, the tumor microenvironment can rescue cancer cells by growth factor mediated induction of pro-survival signaling. We show that EGFR inhibition by Gefitinib is counteracted by several growth factors notably FGF2 and we assessed the global consequences of FGF2-mediated Gefitinib resistance at the proteome and phosphoproteome level. Multiplexed tandem mass tag (TMT) peptide labeling in conjunction with high resolution tandem mass spectrometry allowed the identification and quantification of ~22,000 phosphopeptides and ~8,800 proteins in biological triplicates without missing values. The data shows that Gefitinib treated cells are forced into developing intrinsic resistance by reprogramming of the proteome and phosphoproteome, whereas co-treatment with FGF2 largely reverted these changes to resemble the molecular composition of untreated cells. Simultaneous small molecule EGFR and FGFR inhibition overcomes FGF2 induced Gefitinib resistance and the phosphoproteomic experiments further prioritized the RAS/MEK/ERK axis as well as the PI3K/mTOR axis for combination treatment. Consequently, the MEK inhibitor Trametinib prevented FGF2-mediated survival of EGFR inhibitor resistant cells when used in combination with Gefitinib. Surprisingly, the pase II PI3K/mTOR inhibitor GSK2126458 reversed resistance mediated by all four growth factors tested, making it an interesting candidate for targeting the survival signals provided by the tumor microenvironment.
HostingRepository	PRIDE
AnnounceDate	2022-03-01
AnnouncementXML	Submission_2022-03-01_09:38:31.212.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Heiner Koch
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2016-04-19 01:44:57	ID requested
⏵ 1	2022-03-01 09:38:33	announced

Koch H, Wilhelm M, Ruprecht B, Beck S, Frejno M, Klaeger S, Kuster B, Phosphoproteome Profiling Reveals Molecular Mechanisms of Growth-Factor-Mediated Kinase Inhibitor Resistance in EGFR-Overexpressing Cancer Cells. J Proteome Res, 15(12):4490-4504(2016) [pubmed]

curator keyword: Biomedical

submitter keyword: Gefitinib resistance

Bernhard Kuster
contact affiliation	Chair for Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
contact email	kuster@tum.de
lab head
Heiner Koch
contact affiliation	Technische Universitaet Muenchen
contact email	heiner.koch@tum.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD004007
     1. Label: PRIDE project
     2. Name: Phosphoproteome profiling reveals molecular mechanisms of growth factor mediated kinase inhibitor resistance in cancer cells