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Lookup NU author(s): Dr Natalie TatumORCiD, Professor Ian HicksonORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022, The Author(s). Platinum resistance is a clinical challenge in ovarian cancer. Platinating agents induce DNA damage which activate Mre11 nuclease directed DNA damage signalling and response (DDR). Upregulation of DDR may promote chemotherapy resistance. Here we have comprehensively evaluated Mre11 in epithelial ovarian cancers. In clinical cohort that received platinum- based chemotherapy (n = 331), Mre11 protein overexpression was associated with aggressive phenotype and poor progression free survival (PFS) (p = 0.002). In the ovarian cancer genome atlas (TCGA) cohort (n = 498), Mre11 gene amplification was observed in a subset of serous tumours (5%) which correlated highly with Mre11 mRNA levels (p < 0.0001). Altered Mre11 levels was linked with genome wide alterations that can influence platinum sensitivity. At the transcriptomic level (n = 1259), Mre11 overexpression was associated with poor PFS (p = 0.003). ROC analysis showed an area under the curve (AUC) of 0.642 for response to platinum-based chemotherapy. Pre-clinically, Mre11 depletion by gene knock down or blockade by small molecule inhibitor (Mirin) reversed platinum resistance in ovarian cancer cells and in 3D spheroid models. Importantly, Mre11 inhibition was synthetically lethal in platinum sensitive XRCC1 deficient ovarian cancer cells and 3D-spheroids. Selective cytotoxicity was associated with DNA double strand break (DSB) accumulation, S-phase cell cycle arrest and increased apoptosis. We conclude that pharmaceutical development of Mre11 inhibitors is a viable clinical strategy for platinum sensitization and synthetic lethality in ovarian cancer.
Author(s): Alblihy A, Ali R, Algethami M, Shoqafi A, Toss MS, Brownlie J, Tatum NJ, Hickson I, Moran PO, Grabowska A, Jeyapalan JN, Mongan NP, Rakha EA, Madhusudan S
Publication type: Article
Publication status: Published
Journal: npj Precision Oncology
Year: 2022
Volume: 6
Online publication date: 19/07/2022
Acceptance date: 04/07/2022
Date deposited: 09/01/2024
ISSN (electronic): 2397-768X
Publisher: Nature Research
URL: https://doi.org/10.1038/s41698-022-00298-0
DOI: 10.1038/s41698-022-00298-0
Data Access Statement: Data supporting the study can be found in the supplementary information file, and the corresponding author can make any materials available upon request. Aggregate data from the referenced datasets are available from the corresponding author on reasonable request. Primary datasets generated during the study are available in supplementary tables 7 and 8. Referenced datasets analyzed in the study are described in methods and accession codes are as follows; GSE14764, GSE15622, GSE19829, GSE3149, GSE9891, GSE18520, GSE26712, and TCGA (The Cancer Genome Atlas). The cancer genome atlas (TCGA) ovarian cancer RNAseq gene expression data was accessed from the NCI Genomics Data Commons at the following link: https://portal.gdc.cancer.gov/repository. The full NGS data has been uploaded and is available at NCBI-GEO (https://www.ncbi.nlm.nih.gov/geo/) with the following accession numbers GSE198648 (PEO1, PEO1R cell lines) and GSE160540 (PEO1, PEO1R xenografts).
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