RNA-Seq of PARPi-resistant ovarian cancer cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA988124 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25039467_1.fastq.gz | Fastqsanger.gz | |||
| SRR25039467_2.fastq.gz | Fastqsanger.gz | |||
| SRR25039468_1.fastq.gz | Fastqsanger.gz | |||
| SRR25039468_2.fastq.gz | Fastqsanger.gz | |||
| SRR25039469_1.fastq.gz | Fastqsanger.gz |
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Project description:We have previously established an in vitro model of PARPi-resistant ovarian cancer by long-term exposure of UWB1.289 ovarian cancer cells (and their isogenic derivatives UWB1.289+BRCA1) to incrementally ascending olaparib concentrations. After finalizing this model, we performed RNA-seq, in order to identify differentially expressed transcript in the PARPi-resistant cells, with a focus on genes related to DNA-repair, multi-drug resistance and EMT. As a result, we show that the phenotype of PARPi resistance is associated with EMT-like traits and up-regulation of selective multi-drug related transcripts.
2023-07-31 | GSE235980 | GEO
Project description:Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPi) are approved to treat recurrent ovarian cancer with BRCA1 or BRCA2 mutations, and as maintenance therapy for recurrent platinum sensitive ovarian cancer (BRCA wild-type or mutated) after treatment with platinum. However, the acquired resistance against PARPi remains a clinical hurdle. Our previous study has demonstrated that PARPi can enhance the Aldehyde dehydrogenase (ALDH) activity in ovarian cancer cells, mainly through inducing expression of ALDH1A1, an isoform of the ALDH family. In addition, an ALDH1A1 selective inhibitor can synergize with olaparib in killing EOC cells carrying BRCA2 mutation in both in vitro cell culture and the in vivo xenograft animal model. In order to elucidating the mechanism by which ALDH1A1 renders PARPi resistance to ovarian cancer, we performed RNA-seq analysis to identify genes whose expression can be regulated by ALDH1A1.
2023-07-19 | GSE226018 | GEO
Project description:Bulk RNA-seq of PARPi-resistant cells derived from ovarian cancer cell line PEO1, its parental cell PEO1, and PEO4 cells
2026-07-30 | GSE315090 | GEO
Project description:Transcriptional profiling of EZM8266 treatment in a syngeneic model of PARPi-resistant ovarian cancer.
| PRJNA1114461 | ENA
Project description:Our published data show that electrophilic nitroalkenes (NFAs) selectively kill triple negative breast cancer (TNBC) cells over benign breast epithelial cells. Preliminary data suggests that NFAs are more cytotoxic to TNBC pre-treated with PARP inhibitors (PARPi). In order to better understand PARPi resistance and the impact of NFAs on PARPi-resistant cells, we generated PARPi-resistance in clinically relevant TNBC cell lines, ones that have mutations in the BRCA1 gene. We subsequently performed an RNA-seq analysis to (1) identify changes in gene expression that are associated with PARPi-resistance and (2) identify pathways in PARPi-resistant TNBC that are targeted by NFA-treatment. Preliminary results show that NFA treatment induces significant transcriptomic changes in mutBRCA1 TNBC cells.
2026-08-31 | GSE297522 | GEO
Project description:Role of ALDH1A1 in PARPi resistance in ovarian cancer
| PRJNA938376 | ENA
Project description:Background: PARP inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic. Methods: PARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. STAT3-mediated immunosuppression was investigated in vitro by co-culture experiments and in vivo by analysis of immune cells in the TME of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the anti-tumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and PDX models of ovarian cancer. Results: In this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor associated macrophages (TAMs) in the tumor microenvironment (TME). Markedly increased populations of pro-tumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes pro-tumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of pro-tumor macrophages and increases tumor-infiltrating T-cells upon PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of PD-1 blockade. Conclusions: We elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of pro-tumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonist and overcome PARPi resistance in ovarian cancer.
2025-11-14 | GSE218024 | GEO
Project description:Ovarian cancer is the deadliest gynecological malignancy, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need for novel treatment approaches. Through an unbiased drug screen, we identified the kinase inhibitor, lestaurtinib, as a potent antineoplastic agent for chemotherapy- and PARP-inhibitor (PARPi)-sensitive and -resistant ovarian cancer cells and patient derived xenografts (PDXs). RNA-sequencing revealed that lestaurtinib potently suppressed JAK/STAT signaling and lestaurtinib efficacy was shown to be directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive JAK/STAT pathway activation and genetic loss of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested. This divergent behavior was reflected in the ability of lestaurtinib to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3, whereas ruxolitinib failed to block S727. Consistent with these findings, lestaurtinib additionally inhibited the serine/threonine kinases, JNK and ERK, leading to more complete suppression of STAT phosphorylation. Concordantly, combinatorial treatment with ruxolitinib and a JNK or ERK inhibitor resulted in synergistic antineoplastic effects at dose levels where the single agents were ineffective. Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer.
2025-06-30 | GSE291796 | GEO
Project description:Ovarian cancer is the leading cause of gynecologic cancer-related deaths, with high-grade serous ovarian cancer (HGSOC) being the most common and lethal subtype. While BRCA1/2 mutations are established biomarkers predicting sensitivity to PARP inhibitors (PARPis), a subset of patients with BRCA-proficient HGSOC also respond to PARPi therapy. However, the molecular mechanisms driving PARPi sensitivity in BRCA-proficient tumors remain poorly understood. We hypothesized that the composition of the PARP1 protein complex and PARylation-mediated signaling contribute to PARPi sensitivity or resistance in BRCA-proficient HGSOC. Viability screening of BRCA-proficient ovarian cancer cell lines identified PARPi-sensitive and PARPi-resistant lines. Chemical proteomics using rucaparib revealed enrichment of PARP1, PARP2, and associated binding partners, with notably higher MSH6 levels in sensitive lines. Co-immunoprecipitation further uncovered distinct PARP1–MSH6–PARP2 complex abundance between sensitive and resistant cells. Targeting of MSH6 via CRISPR and siRNA conferred rucaparib resistance, particularly in sensitive lines. To explore downstream signaling, we performed ADP-ribosylation proteomics using clickable NAD⁺ analogs, revealing distinct PARylation profiles between sensitive and resistant lines. CHAF1A, a known MSH6 interactor and PARP1 substrate, was enriched in PARPi-sensitive cells. MSH6 knockdown led to increased CHAF1A expression in both sensitive and resistant lines, regardless of rucaparib treatment. Importantly, CHAF1A silencing significantly impaired cell viability, especially in A2780 cells, and suppressed mTOR signaling, suggesting that CHAF1A acts downstream of MSH6 to regulate the mTOR axis. Furthermore, co-treatment with mTORC1 inhibitors enhanced the cellular effects of rucaparib in resistant cells, underscoring the therapeutic potential of targeting downstream mTOR effectors to overcome intrinsic resistance. In conclusion, this study identifies a novel PARP1–MSH6–CHAF1A axis that regulates PARPi sensitivity via mTOR signaling in BRCA-proficient ovarian cancer. By integrating chemical proteomics and ADP-ribosylation analysis, we delineate the interplay between PARP1 complex composition and signaling dynamics, highlighting MSH6 and CHAF1A as critical modulators of PARPi response and potential biomarkers to enhance therapeutic efficacy in BRCA-proficient HGSOC.
2026-08-21 | PXD067882 | Pride
Project description:<p>Poly(ADP-ribose) polymerase inhibitors (PARPi), such as olaparib, have significantly improved outcomes in ovarian cancer (OC); however, therapy resistance remains a major clinical challenge. Here, we showed that glutamine metabolism was upregulated in PARPi-resistant OC cells and identified the glutamine transporter SLC1A5 as a key mediator of this metabolic adaptation. Inhibition of SLC1A5 increased the sensitivity of OC cells to olaparib both in vitro and in vivo. Mechanistically, we demonstrated that the deubiquitinating enzyme USP14 directly interacted with and stabilized SLC1A5 by removing K48-linked polyubiquitin chains, thereby enhancing glutamine uptake, promoting glutathione synthesis, alleviating oxidative stress, and activating the mTORC1 pathway. This metabolic rewiring improved DNA damage repair capacity and ultimately contributed to PARPi resistance. Notably, combined treatment with the SLC1A5 inhibitor V-9302 and olaparib synergistically suppressed tumor growth in a patient-derived xenograft (PDX) model. Collectively, our findings identify the USP14–SLC1A5 axis as a novel regulator of PARPi resistance and suggest that targeting glutamine metabolism represents a promising therapeutic strategy to overcome PARPi resistance in ovarian cancer.</p>
2026-04-08 | MTBLS14072 | MetaboLights