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FBXW7 mutations in serous endometrial cancers cause increased levels of potentially druggable proteins and in vitro sensitivity to SI-2 and dinaciclib

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Presented at

ESGO State of the Art 2018 Conference

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Abstract

Introduction: Rare, but clinically aggressive endometrial cancers exhibit high frequencies of somatic mutations in the FBXW7 (F-box and WD repeat domain-containing 7) tumor suppressor gene. In fact, somatic FBXW7 mutations have been reported in 17-30% of serous endometrial cancers, 11-28% of uterine carcinosarcomas, and 7-25% of clear cell endometrial cancers. Despite these high frequencies of mutation, the molecular effects of mutated FBXW7 in the context of endometrial cancers have not been determined. Materials and Methods: We introduced six recurrent somatic FBXW7 mutations into serous endometrial cancer cells using transient transfection and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) editing and analyzed expression of potentially druggable proteins using Western blotting. The sensitivity of CRISPR-edited FBXW7-mutant serous endometrial cancer cells to targeted inhibitors was tested using cell viability assays; molecular and cellular effects of the inhibitors were studied using Western blotting, apoptosis assays and flow cytometry. Results: FBXW7 mutations in transiently transfected and CRISPR-edited serous endometrial cancer cells resulted in increased Cyclin E1, steroid receptor coactivator 3 (SRC-3), c-MYC, Rictor, glycogen synthase kinase 3 (GSK3), P70S6 kinase, and protein kinase B (AKT) phosphorylated protein levels. CRISPR-edited FBXW7-mutant serous endometrial cancer cells also exhibited decreased viability in response to SI-2 (a SRC inhibitor) and dinaciclib (a cyclin dependent kinase (CDK) inhibitor) compared to parental cells. Decreased viability was associated with changes in cell cycle distribution and/or increased apoptosis. Conclusion: Our findings provide the first direct biochemical evidence that FBXW7 mutations result in increased levels of potentially druggable proteins in serous endometrial cancer cells and demonstrate that some of these effects confer increased sensitivity to targeted agents in vitro.

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© Copyright 2020 Morressier GmbH.
All rights reserved.