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- W2890984843 abstract "e17089 Background: Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair (HR) genes, so they rely on DNA-damage checkpoint proteins, like the Checkpoint kinase 1 (CHEK1) to induce G2 arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 inhibitors and mitotic Aurora Kinase A and B (AURKA/B) inhibitors. Methods: Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1 and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA/B inhibitor and LY2603618 as CHEK1 inhibitor. Analyses of cell cycle and intracellular mediators were performed by flow cytometry and western-blot. Stem cell properties were evaluated with immunofluorescence. Results: Gene expression analyses followed by functional annotation identified cell cycle as a deregulated function. Identified druggable kinases within this function included AURKA/B, TTK kinase and CHEK1. CHEK1 and AURKA/B inhibitors showed a synergistic interaction in different cellular models. Combination of Alisertib and LY2603618 triggered apoptosis, reduced the stem cell population and increased the effect of taxanes and platinum compounds. AURKA and CHEK1 were amplified in 8.7% and 3.9% of ovarian cancers, respectively. Expression of these genes was linked with detrimental clinical outcome. Conclusions: Amplification of AURKA and CHEK1 was observed in more than 12% of ovarian tumors. Our data describes a synthetic lethality interaction between CHEK1 and AURKA/B inhibitors with potential translation to the clinic." @default.
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- W2890984843 date "2017-05-20" @default.
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- W2890984843 title "Synthetic lethality interaction between aurora kinases and CHEK1 inhibitors in ovarian cancer." @default.
- W2890984843 doi "https://doi.org/10.1200/jco.2017.35.15_suppl.e17089" @default.
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