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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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171516 | GEO | 2021/05/07

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.

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 [WGS]

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.

2021-05-08 | GSE171515 | 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 [exome-seq]

2021-05-08 | GSE171514 | 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 [RNA-seq]

2021-05-08 | GSE171513 | 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

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

| PRJNA719832 | ENA

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]

| PRJNA719836 | ENA

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]

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 [RNA-seq]

| PRJNA719834 | ENA

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: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]

| PRJNA719835 | ENA

Aurora-A promotes the establishment of spindle assembly checkpoint by priming the Haspin-Aurora-B feedback loop in late G2 phase.

Project description:Aurora-A kinase functions mainly in centrosome maturation, separation and spindle formation. It has also been found to be amplified or overexpressed in a range of solid tumors, which is linked with tumor progression and poor prognosis. Importantly, Aurora-A inhibitors are being studied in a number of ongoing clinical trials. However, whether and how Aurora-A has a role in the regulation of the mitotic checkpoint is controversial. Additionally, the function of nuclear-accumulated Aurora-A in late G2 phase is not clear. Here we show that knockout, inhibition or blockade of the nuclear entry of Aurora-A severely decreased the centromere localization of Aurora-B and the phosphorylation of histone H3 threonine 3 (H3T3-ph) mediated by the kinase Haspin in late G2 phase. We further reveal that nuclear-accumulated Aurora-A phosphorylates Haspin at multiple sites at its N-terminus and that this promotes H3T3-ph and the rapid recruitment to the centromere of the chromosomal passenger complex. In addition, Aurora-A facilitates the association of Aurora-B with their common substrates: Haspin and Plk1. Notably, these functions of Aurora-A are mostly independent of Plk1. Thus we demonstrate that, in late G2 and prophase, Aurora-A phosphorylates Haspin to trigger the Haspin-H3T3-ph-Aurora-B positive feedback loop that supports the timely establishment of the chromosomal passenger complex and the mitotic checkpoint before spindle assembly.

| S-EPMC5223110 | biostudies-literature

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.

| S-EPMC4670270 | biostudies-literature

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