PXD008859

PXD008859 is an original dataset announced via ProteomeXchange.

Title	PHLDA1 mediates drug resistance in receptor tyrosine kinase driven cancer
Description	Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks, and represents a critical challenge for precision medicine. Here we show that PHLDA1 down-regulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using FGFR inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by down-regulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 down-regulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2+ breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors, and induction of PHLDA1 expression re-sensitised drug resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance.
HostingRepository	PRIDE
AnnounceDate	2019-03-06
AnnouncementXML	Submission_2019-03-06_02:11:52.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Vinothini Rajeeve
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2018-02-05 07:47:11	ID requested
1	2018-03-05 01:28:09	announced
⏵ 2	2019-03-06 02:11:53	announced	Updated project metadata.

Fearon AE, Carter EP, Clayton NS, Wilkes EH, Baker AM, Kapitonova E, Bakhouche BA, Tanner Y, Wang J, Gadaleta E, Chelala C, Moore KM, Marshall JF, Chupin J, Schmid P, Jones JL, Lockley M, Cutillas PR, Grose RP, PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer. Cell Rep, 22(9):2469-2481(2018) [pubmed]

curator keyword: Biological, Biomedical

submitter keyword: Tyrosine kinase inhibitor, drug resistance, FGF, Akt, Targeted therapy, Cancer

Dr Pedro Cutillas
contact affiliation	Centre for Haemato Oncology Barts Cancer Institute Queen Mary University of London Charter House Square London EC1M 6BQ
contact email	p.cutillas@qmul.ac.uk
lab head
Vinothini Rajeeve
contact affiliation	Centre for Haemato Oncology
contact email	v.rajeeve@qmul.ac.uk
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/2018/03/PXD008859

PRIDE project URI

• PRIDE
  1. PXD008859
     1. Label: PRIDE project
     2. Name: PHLDA1 mediates drug resistance in receptor tyrosine kinase driven cancer