PXD060046

PXD060046 is an original dataset announced via ProteomeXchange.

Title	Multi-omics characterization of acquired Olaparib resistance in BRCA1 and BRCA2 mutant breast cancer cell lines
Description	This is part 2 of the same project. Part 1 was just uploaded with the reference: 1-20250110-174238-3123982. Please merge if possible! Poly (ADP-ribose) polymerase inhibitors (PARPi) are widely used as targeted therapies against breast cancers with BRCA mutations. However, the development of resistance to PARPi poses a significant challenge for these therapies, warranting further need for mechanistic insight into PARPi resitance. Here, we generate and characterize Olaparib resistant (OR) clones of BRCA1/2 mutant breast cancer cell lines MDAMB436 and HCC1428 using a systems-level multi-omics approach, including transcriptome, proteome, phosphoproteome and ADP-ribosylation analysis. Our analyses revealed that resistance development was most strongly driven by protein changes, with modest effects on phosphorylation- and ADP-ribosylation-dependent signaling pathways. We found that BRCA1 expression was reestablished in all OR MDAMB436 clones, whereas PARP1 expression was decreased. In OR HCC1428 clones, BRCA2 function was not restored. However, we saw increased expression of Fanconi anemia group D2 (FANCD2), HPF1 and Nicotinamide phosphoribosyltransferase (NAMPT) in various OR clones, suggesting increased replication fork protection, changes in the ADPr pathway and adaptation of metabolic pathways as a resistance mechanism. Our findings provide valuable insights into the complex landscape of PARPi resistance, offering potential targets for further investigation and therapeutic intervention.
HostingRepository	PRIDE
AnnounceDate	2025-08-26
AnnouncementXML	Submission_2025-08-25_22:57:06.598.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Holda Anagho-Mattanovich
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	adenosine diphosphoribosyl (ADP-ribosyl) modified residue; phosphorylated residue
Instrument	Orbitrap Fusion Lumos; Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-01-21 23:20:55	ID requested
⏵ 1	2025-08-25 22:57:07	announced

Anagho-Mattanovich HA, Mullari M, Anagho-Mattanovich M, Cho H, Pedersen AK, Palasca O, Olsen JV, Locard-Paulet M, Nielsen ML, Multi-omics Characterization of Acquired Olaparib Resistance in BRCA1 and BRCA2 Mutant Breast Cancer Cell Lines. Mol Cell Proteomics, 24(8):101034(2025) [pubmed]

10.1016/j.mcpro.2025.101034;

submitter keyword: Phosphoproteomics, BRCA1/2 mutations, EThcD, ADP-ribosylation, Proteomics, DNA damage, PARP inhibitors,LC-MSMS, Olaparib resistance

Michael L. Nielsen
contact affiliation	Proteomics program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen Current affiliation: Evosep Aps, Denmark
contact email	mln@evosep.com
lab head
Holda Anagho-Mattanovich
contact affiliation	Proteomics program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
contact email	holda.anagho@cpr.ku.dk
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/2025/08/PXD060046

PRIDE project URI

• PRIDE
  1. PXD060046
     1. Label: PRIDE project
     2. Name: Multi-omics characterization of acquired Olaparib resistance in BRCA1 and BRCA2 mutant breast cancer cell lines