ATF6-Mediated Signaling Contributes to PARP Inhibitor Resistance in Ovarian Cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA788907 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR17259574_1.fastq.gz | Fastqsanger.gz | |||
| SRR17259574_2.fastq.gz | Fastqsanger.gz | |||
| SRR17259575_1.fastq.gz | Fastqsanger.gz | |||
| SRR17259575_2.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:High-grade serous ovarian cancer (HGSOC) is the deadliest ovarian cancer histotype due in-part to the lack of therapeutic options for chemotherapy-resistant disease. PARP inhibitors (PARPi) represent a targeted treatment. However, PARPi resistance is becoming a significant clinical challenge. There is an urgent need to overcome resistance mechanisms to extend disease-free intervals. We established isogeneic PARPi-sensitive and -resistant HGSOC cell lines. In three PARPi-resistant models, there is a significant increase in AP-1 transcriptional activity and DNA repair capacity. Using RNA-sequencing and an shRNA screen, we identified activating transcription factor 6 (ATF6) as a mediator of AP-1 activity, DNA damage response, and PARPi resistance. In publicly available datasets, ATF6 expression is elevated in HGSOC and portends a poorer recurrence-free survival. In a cohort of primary HGSOC tumors, higher ATF6 expression significantly correlated to PARPi resistance. In PARPi-resistant cell lines and a PDX model, inhibition of a known ATF6 regulator, p38, attenuated AP-1 activity and RAD51 foci formation, enhanced DNA damage, significantly inhibited tumor burden, and reduced accumulation of nuclear ATF6.ImplicationsThis study highlights that a novel p38-ATF6-mediated AP-1 signaling axis contributes to PARPi resistance and provides a clinical rationale for combining PARPi and AP-1 signaling inhibitors.
| S-EPMC9812934 | biostudies-literature
Project description:PARP inhibitor (PARPi) resistance presents a significant challenge in ovarian cancer treatment, necessitating the development of effective therapeutic strategies to overcome this resistance and improve patient outcomes. Our study demonstrated that elevated expression of SRY-box 9 (SOX9) contributes to olaparib resistance in ovarian cancer. Mechanistically, the deubiquitinating enzyme USP28 was identified as a novel interacting partner of SOX9. USP28 inhibited the ubiquitination and subsequent lysosomal degradation of SOX9, which is mediated by the E3 ubiquitin ligase FBXW7 during olaparib treatment. ChIP-Seq analysis revealed that SOX9 binds to the promoters of key DNA damage response (DDR) genes (SMARCA4, UIMC1, and SLX4), thereby regulating DDR processes in ovarian cancer. Additionally, USP28 promoted olaparib resistance by stabilizing SOX9 protein and enhancing DNA damage repair. Furthermore, the USP28 specific inhibitor AZ1 reduced SOX9 protein stability and increased the sensitivity of ovarian cancer cells to olaparib. In conclusion, targeted inhibition of USP28 promoted ubiquitination-mediated degradation of SOX9, thereby impairing DNA damage repair capabilities and sensitizing ovarian cancer cells to PARPi. These findings elucidate the underlying mechanisms of PARPi resistance in ovarian cancer and suggest the potential efficacy of combining USP28 inhibitors with PARPi to overcome this resistance.
2025-04-23 | GSE271296 | GEO
Project description:Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N6-methyladenosine (m6A) is the most abundant chemical modification of messenger RNA (mRNA). The m6A modification affects RNA fate and functions such as RNA stability. Despite the high initial response rates to PARP inhibitors in BRCA1/2-mutated epithelial ovarian cancers (EOC), PARP inhibitor (PARPi) resistance remains a major challenge. The role of m6A modification in PARPi resistance has not previously been explored. Here we show that m6A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the Wnt/-catenin pathway in BRCA-mutated EOC cells. Global m6A profile reveals a significant increase in m6A modification in FZD10 mRNA. This correlates with an increase in FZD10 mRNA stability and an upregulation of the Wnt/-catenin pathway in PARPi resistant cells. FZD10 knockdown or inhibition of the Wnt/-catenin sensitizes the resistant cells to PARPi. Mechanistically, downregulation of m6A demethylases FTO and ALKBH5 is sufficient to increase FZD10 mRNA m6A modification and reduce PARPi sensitivity, which correlates with an increase in homologous recombination activity. Moreover, PAPRi and Wnt/-catenin inhibitor showed synergistic suppression of growth of PAPRi resistant cells both in vitro and in vivo in a xenograft ovarian cancer mouse model. Our results show that m6A contributes to PAPRi resistance in BRCA-deficient EOC cells by upregulating the Wnt/-catenin pathway through stabilizing FZD10. They also suggest that inhibition of Wnt/-catenin pathway represents a potential strategy to overcome PARPi resistance.
2019-09-14 | GSE119963 | GEO
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
Project description:The recent introduction of poly ADP-ribose polymerase (PARP) inhibitors has significantly improved the survival outcomes of ovarian cancer. This study aimed to identify protein biomarkers and signatures predicting therapeutic responses to PARP inhibitors in high-grade serous ovarian cancer (HGSOC). To identify prognostic biomarkers, we conducted an in-depth proteomic analysis on formalin-fixed paraffin-embedded (FFPE) cancer tissues obtained from 24 HGSOC patients who received PARP inhibitor maintenance therapy for platinum-sensitive recurrence. In total, 7825 proteins were quantified with the tandem mass tag (TMT) labelling method. There were 56 and 131 proteins significantly upregulated in the good and poor response groups, respectively.
2024-05-21 | PXD044703 | Pride
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
Project description:The overall goal of this study was to link AP-1 signaling and DNA damage repair in the context of PARPi resistance
2021-12-21 | GSE190902 | GEO
Project description:CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer
| PRJNA1039833 | ENA
Project description:Inhibition of USP28 sensitizes ovarian cancer to PARP inhibitor through mediating SOX9 deubiquitination
| PRJNA1130878 | ENA
Project description:The N6-methylation of adenosine (m6A) in FZD10 mRNA contributes to PARP inhibitor resistance
| PRJNA490840 | ENA