Similar Datasets
Project 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.
2026-01-05 | PXD057265 | Pride
Project 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.
2026-01-05 | GSE281517 | GEO
Project 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.
2026-01-05 | GSE281519 | GEO
Project description:Lysosomal sequestration of PARP inhibitors drives heterogeneous accumulation in ovarian cancer to increase efficacy
| PRJNA1184717 | ENA
Project description:Lysosomal sequestration of PARP inhibitors drives heterogeneous accumulation in ovarian cancer to increase efficacy [RNA-seq]
| PRJNA1184173 | ENA
Project description:Lysosomal sequestration of PARP inhibitors drives heterogeneous accumulation in ovarian cancer to increase efficacy [Spatial Transcriptomics]
| PRJNA1184175 | ENA
Project description:Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have transformed the ovarian cancer (OC) treatment landscape. This narrative review provides a comprehensive overview of data for the PARPis olaparib, niraparib, and rucaparib in patients with OC and discusses their role in disease management, with a focus on the use of PARPis as maintenance therapy in the United States (US). Olaparib was the first PARPi to be approved as first-line maintenance monotherapy in the US, with maintenance niraparib subsequently approved in the first-line setting. Data also support the efficacy of rucaparib as first-line maintenance monotherapy. PARPi maintenance combination therapy (olaparib plus bevacizumab) also provides benefit in patients with newly diagnosed advanced OC whose tumors tested positive for homologous recombination deficiency (HRD). Biomarker testing is critical in the newly diagnosed setting to identify patients most likely to benefit from PARPi maintenance therapy and guide treatment decisions. Clinical trial data support the use of PARPis (olaparib, niraparib, rucaparib) as second-line or later maintenance therapy in patients with platinum-sensitive relapsed OC. Although distinct differences in tolerability profile were observed between PARPis, they were generally well tolerated, with the majority of adverse events managed by dose modification. PARPis had no detrimental effect on patients' health-related quality of life. Real-world data support the use of PARPis in OC, although some differences between PARPis are apparent. Data from trials investigating novel combination strategies, such as PARPis plus immune checkpoint inhibitors, are awaited with interest; the optimal sequencing of novel therapies in OC remains to be established.
| S-EPMC10344972 | biostudies-literature
Project description:Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most successful examples of clinical translation of targeted therapies in medical oncology, and this has been demonstrated by their effective management of BRCA1/BRCA2 mutant cancers, most notably in breast and ovarian cancers. PARP inhibitors target DNA repair pathways that BRCA1/2-mutant tumours are dependent upon. Inhibition of the key components of these pathways leads to DNA damage triggering subsequent critical levels of genomic instability, mitotic catastrophe and cell death. This ultimately results in a synthetic lethal relationship between BRCA1/2 and PARP, which underpins the effectiveness of PARP inhibitors. Despite the early and dramatic response seen with PARP inhibitors, patients receiving them often develop treatment resistance. To date, data from both clinical and preclinical studies have highlighted multiple resistance mechanisms to PARP inhibitors, and only by understanding these mechanisms are we able to overcome the challenges. The focus of this review is to summarise the underlying mechanisms underpinning treatment resistance to PARP inhibitors and to aid both clinicians and scientists to develop better clinically applicable assays to better select patients who would derive the greatest benefit as well as develop new novel/combination treatment strategies to overcome these mechanisms of resistance. With a better understanding of PARP inhibitor resistance mechanisms, we would not only be able to identify a subset of patients who are unlikely to benefit from therapy but also to sequence our treatment paradigm to avoid and overcome these resistance mechanisms.
| S-EPMC10137187 | biostudies-literature
Project description:Late detection and tumor recurrence are major factors driving the lethality of high-grade serous ovarian carcinoma (HGSOC). PARP inhibitors (PARPi) have achieved significant clinical efficacy by selectively targeting DNA repair deficiencies in HGSOC patients with BRCA mutations and homologous recombination deficiency (HRD). However, a subset of patients ultimately develops resistance to PARPi, necessitating alternative effective treatment options. The mutational signatures of APOBEC3 family of DNA deaminases are widespread across a broad array of cancer types. Here, we report that cancer stem cell (CSC)-like tumorspheres exhibit reduced A3B expression compared to non-CSC adherent counterparts. Importantly, inhibition of A3B leads to PARPi resistance, elevated frequency of CSCs, and enhanced expression of stemness factors. In addition, we found that high A3B-expressing cells are under strong replication stress and thus synchronize efficiently with PARPi. In this study we knocked down of A3B in A2780 3D tumorsphere by lentiviral tranduction, followed by treated of DMSO control or Olaparib, and performed bulk RNA-sequencing to compare gene expression changes (n=3 for each condition).
2025-11-18 | GSE309870 | GEO
Project description:Several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are now in clinical use for tumours with defects in BReast CAncer genes BRCA1 or BRCA2 that result in deficient homologous recombination repair (HRR). Use of olaparib, niraparib or rucaparib for the treatment of high-grade serous ovarian cancer, including in the maintenance setting, has extended both progression free and overall survival for women with this malignancy. While different PARP inhibitors (PARPis) are mechanistically similar, differences are apparent in their chemical structures, toxicity profiles, PARP trapping abilities and polypharmacological landscapes. We have treated ovarian cancer cell line models of known BRCA status, including the paired cell lines PEO1 and PEO4, and UWB1.289 and UWB1.289+BRCA1, with five PARPis (olaparib, niraparib, rucaparib, talazoparib and veliparib) and observed differences between PARPis in both cell viability and cell survival. A cell line model of acquired resistance to veliparib showed increased resistance to the other four PARPis tested, suggesting that acquired resistance to one PARPi may not be able to be rescued by another. Lastly, as a proof of principle, HRR proficient ovarian cancer cells were sensitised to PARPis by depletion of BRCA1. In the future, guidelines will need to emerge to assist clinicians in matching specific PARPis to specific patients and tumours.
| S-EPMC8395221 | biostudies-literature