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Enhanced efficacy of aurora kinase inhibitors in G2/M checkpoint deficient TP53 mutant uterine carcinomas is linked to the summation of LKB1-AKT-p53 interactions [WGS]

ABSTRACT: We report bulk RNA sequencing, low pass whole genome sequencing, and targeted exome sequencing data of six uterine cancer organoids and show how specific molecular defects in these organoids make them sensitive to cell cycle targeting therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171515 | GEO | 2021/05/08

REPOSITORIES: GEO

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Enhanced efficacy of aurora kinase inhibitors in G2/M checkpoint deficient TP53 mutant uterine carcinomas is linked to the summation of LKB1-AKT-p53 interactions [exome-seq]

Project description:We report bulk RNA sequencing, low pass whole genome sequencing, and targeted exome sequencing data of six uterine cancer organoids and show how specific molecular defects in these organoids make them sensitive to cell cycle targeting therapies.

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Enhanced efficacy of aurora kinase inhibitors in G2/M checkpoint deficient TP53 mutant uterine carcinomas is linked to the summation of LKB1-AKT-p53 interactions [RNA-seq]

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Enhanced Efficacy of Aurora Kinase Inhibitors in G2/M Checkpoint Deficient <i>TP53</i> Mutant Uterine Carcinomas Is Linked to the Summation of LKB1-AKT-p53 Interactions.

Project description:Uterine carcinoma (UC) is the most common gynecologic malignancy in the United States. TP53 mutant UCs cause a disproportionate number of deaths due to limited therapies for these tumors and the lack of mechanistic understanding of their fundamental vulnerabilities. Here we sought to understand the functional and therapeutic relevance of TP53 mutations in UC. We functionally profiled targetable TP53 dependent DNA damage repair and cell cycle control pathways in a panel of TP53 mutant UC cell lines and patient-derived organoids. There were no consistent defects in DNA damage repair pathways. Rather, most models demonstrated dependence on defective G2/M cell cycle checkpoints and subsequent upregulation of Aurora kinase-LKB1-p53-AKT signaling in the setting of baseline mitotic defects. This combination makes them sensitive to Aurora kinase inhibition. Resistant lines demonstrated an intact G2/M checkpoint, and combining Aurora kinase and WEE1 inhibitors, which then push these cells through mitosis with Aurora kinase inhibitor-induced spindle defects, led to apoptosis in these cases. Overall, this work presents Aurora kinase inhibitors alone or in combination with WEE1 inhibitors as relevant mechanism driven therapies for TP53 mutant UCs. Context specific functional assessment of the G2/M checkpoint may serve as a biomarker in identifying Aurora kinase inhibitor sensitive tumors.

| S-EPMC8125555 | biostudies-literature

Enhanced efficacy of aurora kinase inhibitors in G2/M checkpoint deficient TP53 mutant uterine carcinomas is linked to the summation of LKB1-AKT-p53 interactions

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-05-07 | GSE171516 | GEO

Enhanced efficacy of aurora kinase inhibitors in G2/M checkpoint deficient TP53 mutant uterine carcinomas is linked to the summation of LKB1-AKT-p53 interactions [WGS]

Project description:Enhanced efficacy of aurora kinase inhibitors in G2/M checkpoint deficient TP53 mutant uterine carcinomas is linked to the summation of LKB1-AKT-p53 interactions [WGS]

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Project description:We performed single nuclei RNA-sequencing (snRNA-seq) with matched T cell receptor sequencing (TCR-seq), and pool matched low pass whole genome sequencing (WGS) of eight specimens from six patients, encompassing four undifferentiated polymorphic sarcomas (UPS) and four intimal sarcomas (INS), and paired specimens from two patients (one UPS and INS each) treated with immune checkpoint blockade (ICB).

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Uterine Carcinomas in Tetrabromobisphenol A-exposed Wistar Han Rats Harbor Increased Tp53 Mutations and Mimic High-grade Type I Endometrial Carcinomas in Women.

Project description:Endometrial carcinoma is the most common gynecologic malignancy is the United States and accounts for 6% of all cancers in women. The disease is classified as type I or type II based on clinicopathologic and molecular features. It is a multifactorial disease with a number of risk factors, including environmental exposures. How environmental exposures, such as flame retardants, may affect the incidence of endometrial cancer is a topic of current and ongoing interest. Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant found in a variety of household products. A recent 2-year National Toxicology Program carcinogenicity study found that exposure to TBBPA was associated with a marked increase in the development of uterine tumors, specifically uterine carcinomas, in Wistar Han rats. Molecularly, TBBPA-induced uterine carcinomas in Wistar Han rats were characterized by a marked increase in tumor protein 53 mutation compared to spontaneous uterine carcinomas, as well as overexpression of human epidermal growth factor receptor 2. Similar to spontaneous carcinomas, tumors in TBBPA-exposed rats were estrogen receptor-alpha positive and progesterone receptor negative by immunohistochemistry. The morphologic and molecular features of uterine carcinomas in TBBPA-exposed rats resemble those of high-grade type I tumors in women, and these data suggest that exposure to TBBPA may pose an increased cancer risk.

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Enhanced efficacy of aurora kinase inhibitors in G2/M checkpoint deficient TP53 mutant uterine carcinomas is linked to the summation of LKB1-AKT-p53 interactions

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Project description:Low coverage whole-genome sequencing have been performed on uterine leiomyosarcoma to uncovered novel potential driver genes and recurrently affected pathways.

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Enhanced efficacy of aurora kinase inhibitors in G2/M checkpoint deficient TP53 mutant uterine carcinomas is linked to the summation of LKB1-AKT-p53 interactions [RNA-seq]

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