PXD057265

PXD057265 is an original dataset announced via ProteomeXchange.

Title	Lysosomal sequestration of PARP inhibitors drives heterogeneous accumulation in ovarian cancer to increase efficacy
Description	PARP inhibitors have had a transformative impact in the treatment of high-grade serous ovarian cancer (HGSOC), but resistance remains a clinical hurdle. Increased expression of ABC drug efflux transporters has been identified as a resistance mechanism in patients but whether intracellular concentrations of these drugs is heterogeneous within tumours remains unclear. We developed a patient-derived explant multi-modal imaging pipeline which demonstrated significant cell-intrinsic heterogeneity of PARP inhibitor accumulation, both between patients and within tumours. Spatial transcriptomics revealed enrichment of apoptotic signatures in high-drug compared to low-drug regions, as well as metabolic and ECM-related differences. While some cases demonstrated a clear anticorrelation of PARP inhibitor levels with MDR1(ABCB1), this was not universal. Rucaparib, an intrinsically fluorescent PARP inhibitor accumulates heterogeneously at the single cell-level in established cell lines, and omics approaches revealed that this is driven by lysosomal sequestration, a pattern also observed in patient samples. Perturbation of lysosomal content altered intracellular levels of rucaparib and niraparib and impacted efficacy suggesting that lysosomes act as a drug reservoir to improve drug response.
HostingRepository	PRIDE
AnnounceDate	2026-01-05
AnnouncementXML	Submission_2026-01-05_12:31:06.873.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alex Montoya
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	2-pyrrolidone-5-carboxylic acid (Gln); acetylated residue; monohydroxylated residue; deamidated residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-28 10:26:47	ID requested
⏵ 1	2026-01-05 12:31:07	announced

Dataset with its publication pending

submitter keyword: Rucaparib,High Grade Serous Ovarian Cancer, ABCB1/MDR1, Niraparib, Spatial Transcriptomics, Patient Derived Explants, Lysosomes, PARP inhibitors, Mass Spectrometry Imaging

Dr Pavel Shliaha
contact affiliation	Head of Proteomics & Metabolomics Facility
contact email	p.shliaha@lms.mrc.ac.uk
lab head
Alex Montoya
contact affiliation	Medical Research Council - London Institute of Medical Sciences
contact email	alex.montoya@lms.mrc.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD057265
     1. Label: PRIDE project
     2. Name: Lysosomal sequestration of PARP inhibitors drives heterogeneous accumulation in ovarian cancer to increase efficacy