BibTex format
@article{Moncayo:2026:10.1038/s41467-026-70558-1,
author = {Moncayo, CR and Restuadi, R and Zhang, G and Marks, D and Ortega-Prieto, P and Doherty, E and Lambie, N and Whilding, C and Andrew, I and Montoya, A and Patel, B and Tyson, K and Pennycook, BR and Pendergast, L and Wu, V and Takats, Z and Matthews, N and Young, GR and Verma, P and Shliaha, P and Game, L and Lenhard, B and Iain, M and Fotopoulou, C and Barr, AR and Cunnea, P and Hall, Z and Fets, L},
doi = {10.1038/s41467-026-70558-1},
journal = {Nature Communications},
title = {Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitors},
url = {http://dx.doi.org/10.1038/s41467-026-70558-1},
volume = {17},
year = {2026}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - 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.
AU - Moncayo,CR
AU - Restuadi,R
AU - Zhang,G
AU - Marks,D
AU - Ortega-Prieto,P
AU - Doherty,E
AU - Lambie,N
AU - Whilding,C
AU - Andrew,I
AU - Montoya,A
AU - Patel,B
AU - Tyson,K
AU - Pennycook,BR
AU - Pendergast,L
AU - Wu,V
AU - Takats,Z
AU - Matthews,N
AU - Young,GR
AU - Verma,P
AU - Shliaha,P
AU - Game,L
AU - Lenhard,B
AU - Iain,M
AU - Fotopoulou,C
AU - Barr,AR
AU - Cunnea,P
AU - Hall,Z
AU - Fets,L
DO - 10.1038/s41467-026-70558-1
PY - 2026///
SN - 2041-1723
TI - Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitors
T2 - Nature Communications
UR - http://dx.doi.org/10.1038/s41467-026-70558-1
VL - 17
ER -