Combination of PARP and KRASG12D Inhibitors Enhances Therapeutic Efficacy by Exploiting Vulnerabilities(scRNA)
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE309596 | GEO | 2025/12/28
REPOSITORIES: GEO
Similar Datasets
Project description:Combination of PARP and KRASG12D Inhibitors Enhances Therapeutic Efficacy by Exploiting Vulnerabilities(scRNA)
| PRJNA1336310 | ENA
Project description:Combination of PARP and KRAS G12D Inhibitors Enhances Efficacy of Therapeutic Vulnerabilities
| PRJNA1174198 | ENA
Project description:To elucidate the molecular basis of the HR deficiency induced by KRASG12D inhibition, we conducted RNA sequencing (RNA-seq) on KRASG12D -mutant PDAC cells (AsPC-1, PANC-1, SW1990) treated with MRTX1133 and KRASG12V -mutant CFPAC-1 cell treated with pan-KRAS inhibitor BI-2865. To futher verified the molecular alternation, we also conducted RNA-seq on KRASG12D-mutant Patient-derived xenograft treated with MRTX1133.
2025-12-28 | GSE279749 | GEO
Project description:Hotspot mutations in the spliceosomal component gene SF3B1 underpin a number of cancers and have a neomorphic function leading to global disruption of canonical splicing and aberrant splicing of hundreds of transcripts. However, the functional consequences of this misplicing and resultant genetic vulnerabilities imposed by these events are poorly understood. Through a synthetic-lethal approach we identify that SF3B1 mutant cells are selectively sensitive to PARP inhibitors. This vulnerability is preserved across multiple cell line and patent derived tumour models, independent of SF3B1 hotspot mutation and is manifested both in vitro and in vivo. These data provide the pre-clinical and mechanistic rationale for assessing SF3B1 mutations as a biomarker of single-agent PARP inhibitor response in a new patient population and may extend the clinical utility of these agents beyond BRCA mutated cancers.
2023-04-19 | PXD019046 | 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 | 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 | GSE281519 | 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 | GSE281517 | GEO
Project description:Next generation sequencing of neuroblastoma (NB) tumors have revealed frequent somatic and germline genetic alterations in genes encoding proteins involved in DNA damage response (DDR) pathways. Despite being well-studied in many adult cancers, roles for DDR disruption in pediatric solid tumors have not been fully elucidated. To address this, patient-relevant loss-of-function mutations in DDR pathway components including Brca2, Atm, and Palb2 were incorporated into an established zebrafish MYCN transgenic model (Tg(dbh:EGFP-MYCN)). These mutations were found to enhance NB formation and metastasis in vivo, and result in upregulation of proliferation, cell cycle checkpoint and DNA damage repair transcriptional signatures, revealing novel molecular vulnerabilities in DDR-deficient NB. Zebrafish DDR-deficient NB and human NB cells with DDR protein knock-down were sensitive to the poly(ADP-ribose)-polymerase (PARP) inhibitor olaparib, and this effect was further enhanced by inhibition of the ataxia telangiectasia and rad3 related (ATR) kinase. Altogether, our data supports a functional role for DDR-deficiency in NB in vivo and therapeutic potential for combination PARP + ATR inhibition in NB patients with alterations in DDR genes.
2025-02-10 | GSE283976 | GEO
Project description:PARP inhibition and the effect on Arabidopsis thaliana high light tolerance
2012-05-01 | E-MTAB-896 | biostudies-arrayexpress
Project description:PARP inhibitors have demonstrated remarkable clinical efficacy in treating ovarian cancer (OV) patients with BRCA1/2 mutations. However, drug resistance inevitably limits their clinical applications and there is an urgent need for improved therapeutic strategies to enhance the clinical utility of PARP inhibitors, such as Olaparib. Here, we present compelling evidence that PARP inhibitor sensitivity is associated with cell cycle dysfunction, independent of homologous recombination deficiency (HRD) /BRCA status. Through high-throughput drug screening with a cell cycle kinase inhibitor library, we identified XL413, a potent CDC7 inhibitor, which can synergistically enhance the anti-cancer efficacy of Olaparib. Mechanistically, we demonstrate that the combined administration of XL413 and Olaparib induced considerable DNA damage and DNA replication stress, leading to increased sensitivity to Olaparib. Additionally, a robust type-I interferon response was triggered through the induction of the cGAS/STING signaling pathway. Using a murine syngeneic tumor model, we further demonstrate that the combination treatment enhanced antitumor immunity, resulting in tumor regression. Collectively, this study presents a novel treatment strategy for patients with advanced OV by combining CDC7 and PARP inhibitiors, offering a promising therapeutic approach forpatients whith limited response to PARP inhibitors.
2024-12-18 | GSE247622 | GEO