Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Combined targeting poly (ADP-ribose) polymerase and receptor tyrosine kinase inhibits ovarian clear cell carcinoma progression through disrupted ribosome biogenesis

ABSTRACT: OCCC has extremely poor prognosis. ARID1A mutation-related chromatin remodeling errors are key molecular features of OCCC. Dysregulation of receptor tyrosine kinases-related signaling pathways is common in OCCC. Here we show that combination of niraparib and lenvatinib exhibits significant synergistic inhibitory effects against platinum–resistant OCCC cells in vitro, in vivo xenografts and prolonged survival in the platinum-refractory patient-derived tumor xenograft (PDX) model. RNA-sequencing revealed the most differently expressed genes in PDX treated with a combination of niraparib and lenvatinib versus control, were in structural ribosomal components. Selected differently expressed ribosomal proteins (RPs: RPS2, RPS5, RPS9 and RPL3) was validated using quantitative polymerase chain reaction. Nucleophosmin (NPM1) expression, which is involved in ribosome biogenesis, was inhibited by niraparib and lenvatinib. Our findings imply that combined niraparib and lenvatinib reduces platinum-resistant OCCC progression by attenuating Src phosphorylation, NPM1 expression and ribosome biogenesis. These results highlight the necessity for continued exploration of this promising treatment strategy, particularly in future clinical trials for platinum-resistant or platinum-refractory OCCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264286 | GEO | 2026/01/28

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other
	GSE264286_counts.txt.gz	Txt

Items per page:

1 - 2 of 2

Similar Datasets

The biological function of GYS1 and p53 in ovarian clear cell carcinoma cell line.

Project description:Ovarian cancer (OC) is a highly fatal and refractory malignancy affecting women, with platinum resistance remaining a major clinical dilemma. Ovarian clear cell carcinoma (OCCC) frequently exhibits increased platinum refractoriness than the other OC subtypes, accompanied by heightened glycogen that engenders clear-cell morphology and wild-type p53. However, their roles in platinum resistance are unclear. Here, we investigated whether glycogen promotes OCCC platinum resistance, and found that GYS1 as a rate-limiting enzyme in glycogen synthesis is clinically associated with poor prognosis and chemoresistance in OCCC. GYS1 is a rate-limiting enzyme in glycogen synthesis, which is clinically associated with poor prognosis and chemoresistance in OCCC. Mechanistically, p53 promotes GYS1 breakdown via upregulating RNF144a, while GYS1 enhances reversed ubiquitination and degradation toward p53 by competitively bound to the USP14, forming a positive feedback circuit. Under platinum stress the accumulated glycogen is mobilized by p53/GYS1 feedback circuit, which fueling energetic NADPH production, hence gaining disulfidptosis invulnerability and increased platinum resistance in OCCC. Collectively, our study identifies glycogen as a contributor to OCCC platinum resistance and elucidates the underlying mechanisms, highlighting a crucial p53/GYS1 positive feedback loop.

2025-09-17 | GSE281988 | GEO

Multiomic analysis implicates OXPHOS/fatty acid oxidation as a potential druggable target in platinum-resistant high grade serous ovarian cancer

Project description:In the United States, high grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy and tumor response to platinum-based chemotherapy is a major determinant of clinical outcome. Although recent efforts have dramatically improved the median survival of advanced ovarian cancer, the initial treatment of the disease has remained the same. The initial therapy includes surgery and chemotherapy and the response rate is very high (85%). Unfortunately, 15% of patients do not respond to this therapy and have platinum-refractory disease. These patients have a very short survival and there is an urgent need to identify novel pharmaceutically targetable pathways to treat these patients. We generated extensive proteomic (global, phospho, ubiquitin, acetylation, pTyr) and RNASeq-based dynamic molecular profiles (+/-carboplatin at 8 and 24 hours) from HGSOC intra-patient cell line pairs (PEA1/PEA2, PEO1/PEO4, PEO14/PEO23) derived from 3 patients before and after acquiring platinum resistance. The molecular profiles revealed a multi-faceted response to carboplatin (e.g., induction of a DNA damage response, ubiquitination of ribosomal proteins, and metabolic changes), as well as novel carboplatin-induced post-translational modifications. Higher oxidative phosphorylation (OXPHOS) and fatty acid beta-oxidation (FAO) pathway expression was observed in resistant compared with sensitive cells. These expression findings were validated via metabolite profiling of cell lines and proteomic profiling of platinum sensitive and refractory HGSOC patient derived xenograft (PDX) models. Both pharmacologic inhibition and CRISPR knockout of CPT1A, which represents the rate limiting step of FAO, sensitizes HGSOC cells to platinum. The metabolic signature identified in the cell line and PDX models is correlated with survival in a previously reported proteomic analysis of HGSOC, and thus FAO is a candidate druggable pathway to overcome platinum resistance.

2021-12-22 | PXD020764 | Pride

Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA Associated Pancreatic Cancer in the Clinical and Pre-clinical Setting

Project description:Germline BRCA-associated pancreatic ductal adenocarcinoma(glBRCA-PDAC) tumors aresusceptible to platinum/PARP-inhibition. The clinical outcomesof 125 glBRCA-PDAC patients was stratified based on the spectrum of response to platinum/PARP-inhibition: i)Refractory(OS<6 months) ii)Durable response followed by acquired-resistance(OS<36 months); iii)Long-term responders(OS>36 months). Patient-derived-xenografts(PDX) were generated from 25 glBRCA-PDAC patients at different clinical time-points. Response to platinum/PARP-inhibition in-vivo and ex-vivo culture(EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA-PDAC and identified homologous recombination(HR)-proficiency and secondary-mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient(HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor-mutational-burden(TMB) was high in HRD-PDAC and significantly higher in tumors with secondary mutations. Anti-PD1 attenuated tumor growth in a novel humanized glBRCA-PDAC PDX-model. This work demonstrates the utility ofpreclinicalmodels, including EVOC, to predict response of glBRCA-PDAC to treatment, whichhas potential to inform time-sensitive medical decisions.

2023-07-13 | GSE235843 | GEO

Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory high grade serous ovarian cancer

Project description:Platinum-based chemotherapies are widely used anti-cancer drugs. Tumor resistance to platinum compounds is a major determinant of patient survival, including in high grade serous ovarian cancer (HGSOC). To understand mechanisms of platinum resistance and identify potential therapeutic targets in resistant HGSOC, we generated a comprehensive, reproducible data resource comprised of dynamic (+/-carboplatin) proteomic/posttranslational modification and RNASeq profiles from HGSOC intra-patient cell line pairs derived from 3 patients before and after acquiring platinum resistance. The molecular profiles revealed extensive responses to carboplatin and differential responses between sensitive and resistant cells. Higher oxidative phosphorylation and fatty acid oxidation (FAO) pathway expression were observed in the platinum-resistant cells, which was further validated in patient-derived xenograft (PDX) models. We show that both pharmacologic inhibition and CRISPR knockout of CPT1A, which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. Thus, FAO is a candidate therapeutic target to overcome platinum resistance.

2022-01-04 | GSE163152 | GEO

RNA-seq of human ovarian clear cell carcinoma PDX tumors

Project description:This dataset contains RNA-seq profiles of patient-derived xenograft (PDX) tumors established from human ovarian clear cell carcinoma (OCCC). Tumor tissues were collected without any therapeutic treatment and used to generate xenografts in immunodeficient mice. Total RNA was extracted from the PDX tumors and sequenced on the Illumina NovaSeq 6000 platform using 150 bp paired-end reads. These data represent the baseline transcriptomic landscape of OCCC tumors and may serve as a resource for studying tumor biology and preclinical model characterization.

2025-12-15 | GSE298088 | GEO

Niraparib treatment of metastatic melanoma in vivo

Project description:Twenty four NSG mice (3 groups, 8 mice/group) were injected subcutaneoulsy with melanoma PDX cells (MM425X). When tumors reached 100mm3, daily i.p. injections of 25mg/kg niraparib were administred to the tumor bearing mice for 30 days. The treatment resulted in significant anti-tumor effects against MM425X. To determine the transcriptomic profiles altered following niraparib treatment, RNA-Seq was performed in MM-425 tumors from three mice treated with niraparib compared with three mice treated with vehicle. To that end, 3 tumors/group (vehicle vs Niraparib treated) were harvested for RNA extraction. RNA extraction from flash-frozen tissue samples was performed as previously described (Olsson et al., 2016, Salomonis et al., 2010, Soroceanu et al., 2013). Total RNA was extracted from PDX tumor tissues using the RNeasy tissue kit (Qiagen) after tissue disruption using ruptor disposable probes and the concentration measured by Qubit RNA HS Assay Kit (ThermoFisher Scientific). RNA-Seq was performed from ~500ng of total RNA processed using TruSeq polyA selection, at a target depth of 40 million paired-end, stranded reads on an Illumina 2500

2021-07-31 | GSE163424 | GEO

Co-administration of MDR1 and BCRP or EGFR/PI3K inhibitors overcomes lenvatinib resistance in hepatocellular carcinoma

Project description:To investigate the mechanism of lenvatinib resistance, we established the lenvatinib resistant Huh7 (Huh7 LR) cells by continuous exposuring to lenvatinib (1–20 μM) for approximately 10 months. We then performed gene expression profiling analysis using data obtained from RNA-seq of Huh7 parental (Huh7 P) cells and the lenvatinib resistant Huh7 (Huh7 LR) cells.

2022-08-26 | GSE211850 | GEO

Discovery proteomics studies for the identification of a protein panel associated with the response to pemetrexed in platinum drug resistant cancer

Project description:Pemetrexed is a drug largely used in lung cancer, mesothelioma and proposed in some cases of ovarian cancers, a particularly severe cancer type. In this latest tumor type, therapy relies on debulking surgery and platinum-based chemotherapy. Despite the initial high response rates to platinum drugs, most patients relapse and die from the disease. Considering the high levels of thymidylate synthase, dhydrofolate reductase and other folate related proteins in platinum drug resistant patients, pemetrexed was proposed as a second line drugs due to its known mechanism of action that engage the mentioned proteins. However a successful outcome could only be expected on the basis of patients’ stratifications. In the present study, a discovery proteomics approach was applied to tissue samples collected beforepemetrexed treatment from platinum resistant patients who relapsed after the first-line carboplatin-based chemotherapy but responded differently to the pemetrexed treatment.

2018-06-06 | PXD007056 | Pride

Gene expression profiling of epithelial ovarian cancer by bulk RNA-seq

Project description:Ovarian cancer has one of the worst prognoses among gynecologic malignancies. About 60% of ovarian cancer cases are diagnosed at Stages III and IV, and their five-year survival rate is less than 30%. Ovarian cancer is classified into four major histological subtypes; serous, clear cell, endometrioid and mucinous. Ovarian clear cell carcinoma (OCCC) is less sensitive to conventional platinum-based chemotherapy and has worse prognosis than other subtypes. In this study, we attempted to identify novel molecular targets critical for the proliferation and tumorigenicity of OCCC using the CRISPR/Cas9 system, and identified some genes as important candidates. Some of these candedates were upregulated in ovarian cancer tissue, especially OCCC. Our results suggest that not only may be these candedates a promising diagnostic maker for OCCC, drugs against these candedates would be useful for the therapeutic treatment of OCCC.

2022-06-08 | GSE189553 | GEO

Gene expression data of ovarian clear cell carcinoma from Singapore

Project description:Ovarian clear cell carcinoma (OCCC) is an epithelial ovarian cancer (EOC) histology having distinct pathology, biology, and molecular footprints. OCCC is chemo-resistant and has the worst stage-adjusted prognosis amongst EOC. Yet, treatment for OCCC patients is no different than other EOC. As OCCC incidence rate has significantly increase in recent decades, it is critical to find OCCC-tailored therapeutic. However, majority of EOC gene expression molecular subtypes (GEMS) studies for personalized medicine focused on the high grade serous histology, and studies in OCCC GEMS were of small sample size. Using more than 200 OCCC gene expression profiles, we identified two OCCC subtypes: EpiCC—epithelial-like, early stage, good prognosis, relative higher rate of gene mutations in SWI/SNF complex; and MesCC—mesenchymal-like, late stage, and poor prognosis. The differential prognosis between EpiCC and MesCC could be observed as early as stage IC. Genetic, copy number and transcriptome profiling showed that both EpiCC and MesCC carried OCCC-associated aberrations. The EpiCC and MesCC are reproducible in validation cohorts and OCCC cell lines. Cell lines assays showed that MesCC is more proliferative and more anoikis resistant than EpiCC. Both EpiCC and MesCC are resistant to cisplatin. Applying the OCCC subtypes to TCGA 534 renal clear cell carcinoma indicated interoperability of the subtyping scheme, and revealed preferential response of EpiCC to sorafenib, and MesCC to bevacizumab. The EpiCC and MesCC classification shows promise in prognostication utility especially for stage IC OCCC patients, and warrants further investigation for subtype-tailored treatment regimen.

2020-01-08 | GSE129617 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data