Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitors Article Swipe
Carmen Ramírez-Moncayo
,
Restuadi Restuadi
,
G.R. Zhang
,
Daniel Marks
,
Paula Ortega-Prieto
,
Emily Doherty
,
Nathalie Lambie
,
Chad Whilding
,
Ivan Andrew
,
Alex Montoya
,
Bhavik Patel
,
Betheney R. Pennycook
,
Vincen Wu
,
Zoltán Takáts
,
Nik Matthews
,
George R. Young
,
Pavel V. Shliaha
,
Laurence Gamé
,
Boris Lenhard
,
Iain A. McNeish
,
Christina Fotopoulou
,
Alexis R. Barr
,
Paula Cunnea
,
Zoe Hall
,
Louise Fets
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.05.31.656628
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.05.31.656628
For all drugs, effective target engagement requires sufficient intracellular concentrations of drug to be reached, but whether tumour heterogeneity impacts drug distribution and efficacy is poorly studied. PARP inhibitors have transformed treatment of high-grade serous ovarian carcinoma (HGSOC), but resistance remains a clinical hurdle in this highly heterogeneous tumour type. We developed a patient-derived explant multi-modal imaging pipeline, which demonstrated that cell-intrinsic PARP inhibitor accumulation is highly variable, both between patients and within tumours. Spatial transcriptomics revealed enrichment of apoptotic and lysosomal signatures in ‘high-drug’ regions. Rucaparib, an intrinsically fluorescent PARP inhibitor, accumulates heterogeneously at the single-cell level, with ‘rucaparib-high’ cells demonstrating increased drug response relative to ‘rucaparib low’. Mechanistically, lysosomal sequestration creates a rucaparib reservoir that determines drug levels in the nucleus. Perturbation of lysosomal content altered intracellular levels of weak base PARP inhibitors rucaparib and niraparib, but not olaparib. Together these data suggest that lysosomes act as a reservoir for a subset of PARP inhibitor drugs to improve drug response.
Related Topics
Concepts
Distribution (mathematics)
Poly ADP ribose polymerase
Drug
Computer science
Chemistry
Pharmacology
Medicine
Biochemistry
Mathematics
Enzyme
Mathematical analysis
Polymerase
Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.05.31.656628
- https://www.biorxiv.org/content/biorxiv/early/2025/06/03/2025.05.31.656628.full.pdf
- OA Status
- green
- References
- 56
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4411034965
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4411034965Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2025.05.31.656628Digital Object Identifier
- Title
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Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitorsWork title
- Type
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preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
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2025Year of publication
- Publication date
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2025-06-03Full publication date if available
- Authors
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Carmen Ramírez-Moncayo, Restuadi Restuadi, G.R. Zhang, Daniel Marks, Paula Ortega-Prieto, Emily Doherty, Nathalie Lambie, Chad Whilding, Ivan Andrew, Alex Montoya, Bhavik Patel, Betheney R. Pennycook, Vincen Wu, Zoltán Takáts, Nik Matthews, George R. Young, Pavel V. Shliaha, Laurence Gamé, Boris Lenhard, Iain A. McNeish, Christina Fotopoulou, Alexis R. Barr, Paula Cunnea, Zoe Hall, Louise FetsList of authors in order
- Landing page
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https://doi.org/10.1101/2025.05.31.656628Publisher landing page
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-
https://www.biorxiv.org/content/biorxiv/early/2025/06/03/2025.05.31.656628.full.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
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https://www.biorxiv.org/content/biorxiv/early/2025/06/03/2025.05.31.656628.full.pdfDirect OA link when available
- Concepts
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Distribution (mathematics), Poly ADP ribose polymerase, Drug, Computer science, Chemistry, Pharmacology, Medicine, Biochemistry, Mathematics, Enzyme, Mathematical analysis, PolymeraseTop concepts (fields/topics) attached by OpenAlex
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0Total citation count in OpenAlex
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56Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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