PXD021726

PXD021726 is an original dataset announced via ProteomeXchange.

Title	LC-MS/MS identification of differentially expressed proteins in carboplatin resistant Triple Negative Breast Cancer
Description	Triple negative breast cancer (TNBC) is the subtype of breast cancer most lacking in efficient treatment options. Although many TNBCs show remarkable responses to carboplatin-based chemotherapy, they often develop resistance over time. With increasing use of carboplatin in clinics, there is a pressing need to understand mechanisms causing carboplatin resistance and identify the vulnerabilities of carboplatin-resistant tumors. We generated carboplatin-resistance models based on the TNBC cell line MDA-MB-468 and patient derived xenograft (PDX) models of TNBCs. By combining the results of mass spectrometry-based proteome profiling and a kinome RNA interference screen, we assessed the molecular changes and vulnerabilities of carboplatin-resistant TNBCs. Using pharmacological inhibition of the identified targets, we validated the dependencies of carboplatin-resistant cells in vitro and in PDX models. We found that carboplatin resistance in TNBC is accompanied by drastic proteome rewiring. Carboplatin-induced metabolism alterations and upregulation of anti-oxidative response keep low levels of DNA damage and support cell replication in the presence of carboplatin. Carboplatin-resistant cells also exhibited longer mitosis due to dysregulation of mitotic checkpoint. Whereas the components of the mitotic checkpoints, AURKA and BUB1, are essential for the viability of carboplatin-resistant cells, the checkpoint kinases CHEK1 and WEE1 are indispensable for survival of carboplatin-treated resistant cells. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Abrogation of the mitotic checkpoint re-sensitizes carboplatin-resistant TNBCs to carboplatin. CHEK1 inhibition represents a potential strategy for the treatment of carboplatin-resistant TNBCs.
HostingRepository	PRIDE
AnnounceDate	2021-07-07
AnnouncementXML	Submission_2021-07-06_23:15:42.879.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Delphi Van Haver
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-09-28 23:24:34	ID requested
⏵ 1	2021-07-06 23:15:44	announced

Moens S, Zhao P, Baietti MF, Marinelli O, Van Haver D, Impens F, Floris G, Marangoni E, Neven P, Annibali D, Sablina AA, Amant F, The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers. Sci Rep, 11(1):3176(2021) [pubmed]

submitter keyword: LC-MS/MS identification of differentially expressed proteins in carboplatin resistant Triple Negative Breast Cancer

Frederic Amant
contact affiliation	Gynecological Oncology Laboratory, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), 3000 Leuven, Belgium / Department of Obstetrics and Gynecology, University Hospitals Leuven and Department of Oncology, 3000 Leuven, Belgium / Centre for Gynecologic Oncology Amsterdam (CGOA), Antoni Van Leeuwenhoek-Netherlands Cancer Institute (AvL-NKI), University Medical Center (UMC), Amsterdam, The Netherlands
contact email	frederic.amant@uzleuven.be
lab head
Delphi Van Haver
contact affiliation	VIB Proteomics Core
contact email	delphi.vanhaver@vib-ugent.be
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/2021/07/PXD021726

PRIDE project URI

• PRIDE
  1. PXD021726
     1. Label: PRIDE project
     2. Name: LC-MS/MS identification of differentially expressed proteins in carboplatin resistant Triple Negative Breast Cancer