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LINC00467 Mediates PARP Inhibitor Resistance in High-grade Serous Ovarian Cancer by Regulating miR-485-5p/RAD50 axis

ABSTRACT: To investigate the essential gene associated with PARP inhibitor response， we established PARP inhibitor resistance SKOV3 cell line and RNA-seq was performed to confirm the differentially expressed gene

ORGANISM(S): Homo sapiens

PROVIDER: GSE208356 | GEO | 2025/07/01

REPOSITORIES: GEO

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LINC00467 Mediates PARP Inhibitor Resistance in High-grade Serous Ovarian Cancer by Regulating miR-485-5p/RAD50 axis

Project description:LINC00467 Mediates PARP Inhibitor Resistance in High-grade Serous Ovarian Cancer by Regulating miR-485-5p/RAD50 axis

| PRJNA859672 | ENA

Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma

Project description:Ovarian high-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer with limited therapeutic options. In recent years, PARP inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Therapies disrupting the spliceosome alter cancer transcriptomes and have shown potential to improve PARP inhibitor response. Indisulam (E7070) has been identified as a molecular glue that brings splicing factor RBM39 and DCAF15 E3 ubiquitin ligase in close proximity. Exposure to indisulam induces RBM39 proteasomal degradation through DCAF15-mediated polyubiquitination and subsequent RNA splicing defects. In this study, we demonstrate that loss of RBM39 induces splicing errors in DNA damage repair genes in ovarian cancer, leading to increased sensitivity to PARP inhibitors such as olaparib. Indisulam synergized with olaparib in multiple in vitro models of ovarian cancer regardless of PARP inhibitor sensitivity and improved olaparib response in mice bearing PARP inhibitor-resistant tumors. DCAF15 expression, but not BRCA1/2 mutational status, was essential for the synergy between indisulam and olaparib, suggesting that the combination therapy may benefit patients irrespective of their BRCA1/2 status. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improving PARP inhibitor response in ovarian HGSC

2023-01-22 | GSE223011 | GEO

PARP inhibitors differentially regulate immune responses in distinct genetic backgrounds of high-grade serous tubo-ovarian carcinoma

Project description:Immune checkpoint inhibitors (ICIs) have revolutionized treatment for several tumor indications without demonstrated benefit for ovarian cancer patients. To improve the therapeutic ratio of ICIs in ovarian cancer patients, several different clinical trials are testing combinations with poly (ADP-ribose) polymerase (PARP) inhibitors. Comparing the immunomodulatory effects of clinically advanced PARP inhibitors may help to identify the best partner to combine with ICIs. We examined the treatment effect of talazoparib (a PARP trapper) and veliparib (a solely PARP enzymatic inhibitor) in homologous recombination deficient (HRD) and homologous recombination proficient (HRP) high-grade serous tubo-ovarian carcinoma (HGSC) cell lines on immune-related gene expression. We discovered and validated that CXCL8, IL-6, and TNF gene expression were upregulated after talazoparib treatment in both OVCAR3 (HRD) and CAOV3 (HRP) HGSC cell lines. In contrast, veliparib treatment slightly elevated similar genes exclusively in a HRD HGSC cell line model. We expanded these studies to include olaparib, a PARP trapper less potent than talazoparib, and found effects specific to COV361 (BRCA1 mutant) and OVCAR8 (BRCA1 methylated) HGSC cells but not all HRD HGSC cell lines. Our studies also identified differences among PARP trappers versus veliparib on augmenting CXCL10 expression. Finally, we show that talazoparib modulates the CXCL10 response in cGAS-defective cell lines, independent of the cGAS-STING pathway. These mechanistic studies advance our understanding of how different PARP inhibitors affect the immune system in various genetic backgrounds.

2025-01-03 | GSE285827 | GEO

Transcriptional profiling of EHMT1/2 depletion and overexpression in various high grade serous ovarian cancer models

Project description:Euchromatin methyltransferase1/2 (EHMT1/2) have been correlated with tumorigenesis and therapy resistance through unknown mechanisms of action. Using a combination of experimental and bioinformatic analyses in several PARP inhibitor resistant ovarian cancer models, we demonstrate that combinatory EHMT and PARP inhibition is effective in treating PARP inhibitor resistant ovarian cancers. Our in vitro studies show that combinatory therapy reactivates transposable elements and increased immunostimulatory dsRNA formation and several immune signaling pathways. Our in vivo studies show that single EHMT and combinatory EHMT and PARP inhibition reduces tumor burden and that this reduction is dependent on CD8 T cells. Together, our results show a direct mechanism by which transposable elements are regulated and how an epigenetic therapy can be used as a fine tune agent to treat cancers with specific genetics.

2023-06-14 | GSE225338 | GEO

Amplification of mutant BRCA2 gene confers resistance to PARP inhibitor

Project description:Breast cancer gene 2 (BRCA2) deleterious mutations confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to its critical role in DNA repair. PARP inhibitor Olaparib is now approved and several other PARP inhibitors are now in different stages of clinical trials. Development of resistance to PARP inhibitors limits their clinical utility. The mechanism of resistance remains not fully understood. Here we show that amplification of mutant BRCA2 confers PARP inhibitor resistance. The amplification of mutant BRCA2 gene copies correlates with an increase in mutant BRCA2 expression and an increase in the levels of its interacting proteins PALB2 and RAD51. In addition, homologous recombination mediated DNA repair is rescued in these cells as evidenced by the formation of RAD51 focus formation. The overexpressed mutant BRCA2 is essential for the observed PARP inhibitor resistance because knockdown of its expression is sufficient to re-sensitize these cells to PARP inhibition. Collectively, our results indicate a new mechanism of resistance to PARP inhibitor in BRCA2 mutant cancer cells

2017-09-02 | GSE86394 | GEO

Characterization of a RAD51C-Silenced High Grade Serous Ovarian Cancer Model During PARP Inhibitor Resistance Development

Project description:Characterization of a RAD51C-Silenced High Grade Serous Ovarian Cancer Model During PARP Inhibitor Resistance Development

| PRJNA693039 | ENA

PARP inhibitors in platinum-sensitive high-grade serous ovarian cancer.

Project description:PURPOSE:Poly(ADP-ribose) polymerase inhibitors (PARPi) have changed the management of high-grade serous ovarian cancer (HGSOC). The rationale for the development of PARPi was based on the concept of synthetic lethality, in which a cell can survive a deficiency of one gene/gene product, but may die if there is a deficiency in a combination of genes/gene products. In women with BRCA1/2 deficiency within their ovarian cancer tissue, inhibition of PARP imposes an intolerable burden of DNA damage repair deficiency and may induce cell death. METHODS:Clinical trials have evaluated PARPi as single-agent therapeutics and as maintenance treatment following platinum-based chemotherapy for HGSOC. Clinical data suggest the most impressive anti-tumour activity occurs in women with platinum-sensitive ovarian cancer and germline or somatic BRCA1/2 mutations (g/sBRCAmt). RESULTS:In the maintenance setting, randomised trials have shown that PARPi compared to placebo reduce the hazard ratio for the development of progressive disease to 0.2-0.27 for patients with a g/sBRCAmt; to 0.34-0.38 for patients with putative evidence of DNA damage repair deficiency; and to 0.35-0.45 in an unselected population with HGSOC. Furthermore, phase 1/2 trials have reported single-agent anti-tumour response rates in gBRCAmt of approximately 50% in platinum-sensitive and 25% in platinum-resistant disease. CONCLUSION:Here, we discuss the evidence for the use of PARPi as single-agent therapeutics and maintenance treatment in HGSOC and evaluate the genetic assays used in clinical trials so far. We discuss the emerging role of platinum sensitivity as a broad eligibility criteria for the use of PARPi.

| S-EPMC5854713 | biostudies-literature

Parp-1 wildtype and deficient mouse embryonic stem cells

Project description:Genome-wide methylation analysis was performed by methylated DNA immunoprecipitation (MeDIP)-CpG island (CGI) microarray analysis to identify the CpG methylation levels of Parp-1 wildtype, Parp-1 deficient or Parp inhibitor treated mouse embryonic stem cells.

2014-12-31 | GSE37651 | GEO

Proteomic analysis reveals low dose PARP inhibitor-induced differential protein expression in BRCA1-mutated high-grade serous ovarian cancer cells

Project description:To detect the off-target effects of PARP inhibition, a quantitative mass spectrometry-based proteomic analysis was conducted of a BRCA1-mutated HGSOC cell line treated with low doses of two PARPi, Niraparib and Rucaparib.

2022-04-15 | PXD027177 | Pride

PARP inhibition

Project description:PARP inhibition and the effect on Arabidopsis thaliana high light tolerance

2012-05-01 | E-MTAB-896 | biostudies-arrayexpress