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Lestaurtinib inhibits therapy resistant ovarian cancer

ABSTRACT: Lestaurtinib inhibits therapy resistant ovarian cancer

PROVIDER: PRJNA1235256 | ENA |

REPOSITORIES: ENA

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Lestaurtinib inhibits therapy resistant ovarian cancer

Project description:Ovarian cancer is the deadliest gynecological cancer, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need to devise novel therapeutic strategies. Through an unbiased drug screen, we identified lestaurtinib as a potent inhibitor of chemotherapy- and poly-ADP ribose polymerase inhibitors (PARPi)-sensitive and -resistant ovarian cancer cells and patient-derived xenografts (PDXs). RNA-sequencing revealed that lestuartinib potently suppressed JAK/STAT signaling. Lestaurtinib efficacy was directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive activation of this pathway and genetic ablation of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib displayed synergy with cisplatin and olaparib, including in a model of PARPi resistance. Interestingly, the most well-known JAK/STAT inhibitor, ruxolitinib, completely failed to inhibit any cell line or PDX model tested. This drug-specific discrepancy was related to STAT phosphorylation profiles where lestaurtinib was shown to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3 whereas ruxolitinib failed to block S727. Mechanistically, lestaurtinib additionally inhibited JNK and ERK activity, leading to broad suppression of STAT phosphorylation. However, combining ruxolitinib with a JNK or ERK inhibitor was synergistic at dose levels where single agents were ineffective. Taken together, these findings indicate that lestaurtinib, or other monotherapy or combinatorial strategies that converge on JAK/STAT signaling, is 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

KFTX paclitaxel (PTX)-resistant ovarian cancer cells, KFTXlow PTX-resistant ovarian cancer cells and KFlow PTX-sensitive ovarian cancer cells expression profilies

Project description:KFTX paclitaxel (PTX)-resistant ovarian cancer cells, KFTXlow PTX-resistant ovarian cancer cells and KFlow PTX-sensitive ovarian cancer cells expression profilies

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Transcriptional profiling of EZM8266 treatment in a syngeneic model of PARPi-resistant ovarian cancer.

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.

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RNA-Seq of PARPi-resistant ovarian cancer cells

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.

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Expression profiling of cisplatin resistant derivatives of ovarian cancer cell line A2780

Project description:The goal of this study was to determine genes with altered expression after selection of ovarian cancer cells for survival in increasing concentrations of cisplatin. A series of progressively cispatin resistant derivatives of A2780 ovarian cancer cell lines was hybridized to spotted cDNA microarrays using two color technology using the parental A2780 cells as a reference. Duplicate hybridizations were carried out for each resistant derivative.

2013-12-22 | E-GEOD-44022 | biostudies-arrayexpress

RNA-Seq of PARPi-resistant ovarian cancer cells

Project description:RNA-Seq of PARPi-resistant ovarian cancer cells

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KFTX paclitaxel (PTX)-resistant ovarian cancer cells, KFTXlow PTX-resistant ovarian cancer cells and KFlow PTX-sensitive ovarian cancer cells expression profilies

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Targeting p85β condensates by RNA therapy inhibits liver cancer progression

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aCGH profiles of parental and oxaliplatin resistant colorectal cancer and ovarian cancer cell lines

Project description:Oxaliplatin resistance was induced in 2 colorectal cancer cell lines (LoVo-92, wt-p53 and LoVo-Li, functionally inactive p53) and one ovarian cancer cell line (A2780, wt-p53). Resistance was induced by weekly exposure to oxaliplatin for 4 hrs or 72 hrs with increasing concentrations for a period of 7 months Genomic DNA of oxaliplatin and cisplatin resistant colorectal cancer and ovarian cancer cell lines as well as the parental cell lines were labeled and subsequently hybridized against pooled reference DNA of healthy volunteers of the opposite gender using across array hybridization. Extracted raw-data were normalised and smoothend using the R-script NOWAVE resulting in normalised log2 ratio profiles of resistant cell line versus parental cell line and parental cell line versus reference DNA.

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