Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitors

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. Poly (ADP-ribose) polymerase (PARP) inhibitors have transformed treatment opportunities for women with high-grade serous ovarian carcinoma, but resistance remains a clinical hurdle in this highly heterogeneous tumour type. Here, we present a patient-derived explant multi-modal imaging pipeline, which demonstrates that cell-intrinsic PARP inhibitor accumulation is highly variable, both between patients and within tumours. Spatial transcriptomics reveals 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 alters 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.

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Publication Details

Journal
Nature Communications
Published
2026-03-17
DOI
https://doi.org/10.1038/s41467-026-70558-1
Primary Topic
PARP inhibition in cancer therapy
Type
article
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article

Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitors

Chad Whilding, Pavel V. Shliaha, Paula Ortega-Prieto, Vincen Wu et al.
Nature Communications
PARP inhibition in cancer therapy
article

Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitors

Chad Whilding, Pavel V. Shliaha, Paula Ortega-Prieto, Vincen Wu, Betheney R. Pennycook, Boris Lenhard, Bhavik Patel, Alex Montoya, Louise Fets, Nik Matthews, Ivan Andrew, Restuadi Restuadi, Paula Cunnea, George R. Young, Iain A. McNeish, Nathalie Lambie, Carmen Ramirez Moncayo, Laurence Gamé, Katie Tyson, Emily Doherty, Christina Fotopoulou, Daniel Marks, Priyanka Verma, Zoe Hall, Lauren Pendergast, Alexis R. Barr, Guanying Zhang, Zoltan Takats
article en

Abstract

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. Poly (ADP-ribose) polymerase (PARP) inhibitors have transformed treatment opportunities for women with high-grade serous ovarian carcinoma, but resistance remains a clinical hurdle in this highly heterogeneous tumour type. Here, we present a patient-derived explant multi-modal imaging pipeline, which demonstrates that cell-intrinsic PARP inhibitor accumulation is highly variable, both between patients and within tumours. Spatial transcriptomics reveals 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 alters 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.

Nature Communications
Washington University in St. Louis (US), NIHR Imperial Biomedical Research Centre (GB), Genomics (United Kingdom) (GB), MRC London Institute of Medical Sciences (GB), Imperial College London (GB)
Good health and well-being
Openalex Percentile: Top 19%
PARP inhibition in cancer therapy
DOIOpen Access PDFOpenAlex
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