Mitotic MTH1 Inhibitor Karonudib Kills Epithelial Ovarian Cancer Independent of Platinum Sensitivity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1245156 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The prognosis for women with ovarian cancer (OC) is particularly poor if resistance to platinum compounds, the mainstay of standard-of-care OC therapy, develops. Inhibitors of the Nudix hydrolase MuT homolog 1 (MTH1) have previously been shown to arrest cancer cells in mitosis, increase 8-oxo-2’-deoxyguanosine (8-oxo-dG) incorporation into DNA, and selectively kill neoplastic cells while sparing normal cells. Here we explored the cytotoxic mechanism of these agents as well as their activity against platinum-resistant OC in vitro and in vivo. Two mitotic MTH1 inhibitors (mMTH1is), TH588 and karonudib, decreased colony formation and induced cell death in both platinum-sensitive OC cell lines and their platinum-resistant counterparts in vitro but had limited effects on fallopian tube and immortalized ovarian surface epithelial cells. Treatment with karonudib stalled OC cells in mitosis and caused elevated 8-oxo-dG levels in DNA. Cytotoxicity of this agent was blunted by overexpression of the pre-mitotic checkpoint protein CHFR, which inhibits other anti-mitotics, or treatment with the antioxidant N-acetylcysteine, which diminishes nuclear 8-oxo-dG staining, suggesting a role for both mitotic stalling and increased nuclear incorporation of oxidized nucleotides in karonudib efficacy. In three orthotopic OC patient-derived xenograft models, karonudib induced growth delay in vivo. Moreover, addition of karonudib to carboplatin doubled median overall survival in two models and prolonged survival for the duration of the study (110 days) in the third. These results, which demonstrate activity of mMTH1 as monotherapy and in combination with carboplatin in OC, suggest that karonudib-based combinations warrant further investigation as potential therapies for platinum-resistant OC.
2025-07-02 | GSE293549 | GEO
Project description: Not available
| S-EPMC12183885 | biostudies-literature
Project description:Cholesterol homeostasis modulates platinum sensitivity in human ovarian cancer
| PRJNA603116 | ENA
Project description:Here we show that platinum-resistant ovarian cancer cells also show reduced cholesterol biosynthesis, and mostly rely on uptake of exogenous cholesterol for their needs. Expression of FDPS and OSC, enzymes involved in cholesterol synthesis, are decreased both in drug-resistant cells and upon TRAP1 silencing, whereas the expression of LDL receptor, the main mediator of extracellular cholesterol uptake, is increased. Strikingly, treatment with different statins to inhibit cholesterol synthesis reduces cisplatin-induced apoptosis, whereas silencing of LIPG, an enzyme involved in lipid metabolism, increases sensitivity to the drug.
2020-05-21 | GSE144248 | GEO
Project description:Large independent analyses on cancer cell lines followed by functional studies have identified Schlafen 11 (SLFN11), a putative helicase, as the strongest predictor of sensitivity to DNA-damaging agents (DDA), including platinum. However, its role as a prognostic biomarker is undefined, partially due to the lack of validated methods to score SLFN11 in human tissues. Here, we implemented a pipeline to quantify SLFN11 in human cancer samples. By analyzing a cohort of high-grade serous ovarian carcinoma (HGSOC) specimens prior platinum-based chemotherapy treatment, we show, for the first time, that SLFN11 density in both the neoplastic and microenvironmental components was independently associated with favorable outcome. We observed SLFN11 expression in both infiltrating innate and adaptive immune cells, and analyses in a second, independent, cohort revealed that SLFN11 is associated with immune activation in HGSOC. We found that platinum treatments activated immune-related pathways in ovarian cancer cells in a SLFN11-dependent manner, representative of tumor-immune transactivation. Moreover, SLFN11 expression was induced in activated, isolated, immune cell subpopulations, hinting that SLFN11 in the immune compartment may be an indicator of immune transactivation. In summary, we propose SLFN11 is a dual biomarker capturing simultaneously interconnected immunological and cancer-cell-intrinsic functional dispositions associated with sensitivity to DDA treatment.
2021-07-13 | GSE179896 | GEO
Project description:MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells
| PRJEB62092 | ENA
Project description:The B-MYB-MuvB (MMB) complex is a key regulator of mitotic gene expression and is activated upon inhibition of the ATR-CHK1 pathway, resulting in premature mitotic entry, replication catastrophe, and cell death. Here we identify the transcriptional co-factor TRRAP as a critical regulator of MMB-dependent mitotic transcription. TRRAP physically interacts with B-MYB and is required for the expression of MMB target genes during both normal G2/M progression and CHK1-inhibitor-induced premature mitosis. These results identify TRRAP as a critical chromatin co-factor for MMB-driven mitotic transcription, linking chromatin regulation to checkpoint sensitivity and highlighting a potential vulnerability in cancer cells.
2026-06-19 | GSE318655 | GEO
Project description:Platinum compounds display clinical activity against a wide variety of solid tumors. However, resistance to these agents is a major limitation in cancer therapy. Reduced platinum uptake and increased platinum export are examples of resistance mechanisms that limit the extent of DNA damage. Here, we report the discovery and characterization of the role of ATP11B, a P-type ATPase membrane protein, in cisplatin resistance. ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro. Combined therapy of cisplatin and ATP11B-siRNA significantly decreased cancer growth in mice bearing ovarian tumors derived from cisplatin-sensitive and -resistant cells. In vitro mechanistic studies on cellular platinum content and cisplatin efflux-kinetics indicated that ATP11B enhances the export of cisplatin from cells. The co-localization of ATP11B with fluorescent cisplatin and with vesicular trafficking proteins such as syntaxin-6 (STX6) and vesicular associated membrane protein 4 (VAMP4) strongly suggests that ATP11B contributes to secretory vesicular transport of cisplatin from Golgi to plasma membrane. In conclusion, silencing ATP11B expression might be a therapeutic strategy to overcome cisplatin resistance. We performed the transfection of control-siRNA and ATP11B-siRNA to both cisplatin-sensitive A2780-PAR and cisplatin-resistant A2780-CP20 cells respectively.
2013-01-23 | E-GEOD-43694 | biostudies-arrayexpress
Project description:The objective of this work was to identify potential cancer biomarkers by analyzing microarray and protein expression data from platinum-sensitive and -resistant ovarian cancer patient samples. The gene expression profiles of the samples were ompared based on platinum sensitivity status and PARP levels.
2018-05-09 | GSE114206 | GEO