2. Academic Validation
  3. Selective Killing of BRCA2-Deficient Ovarian Cancer Cells via MRE11 Blockade

Selective Killing of BRCA2-Deficient Ovarian Cancer Cells via MRE11 Blockade

  • Int J Mol Sci. 2023 Jun 30;24(13):10966. doi: 10.3390/ijms241310966.
Adel Alblihy 1,  Reem Ali 1,  Mashael Algethami 1,  Alison A Ritchie 1,  Ahmed Shoqafi 1,  Shatha Alqahtani 1,  Katia A Mesquita 1,  Michael S Toss 1,  Paloma Ordóñez-Morán 1,  Jennie N Jeyapalan 1 2,  Lodewijk Dekker 3,  Martina Salerno 4,  Edgar Hartsuiker 4,  Anna M Grabowska 1,  Emad A Rakha 1 5,  Nigel P Mongan 1,  Srinivasan Madhusudan 1 6
Affiliations

Affiliations

  • 1 Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham NG7 3RD, UK.
  • 2 Faculty of Medicine and Health Sciences, University of Nottingham, Sutton Bonington Campus, Sutton Bonington LE12 5RD, UK.
  • 3 Nottingham Biodiscovery Institute, School of Pharmacy, University of Nottingham, Nottingham NG7 3RD, UK.
  • 4 North West Cancer Research Institute, School of Medical and Health Sciences, Bangor University, Bangor LL57 2UW, UK.
  • 5 Department of Pathology, Nottingham University Hospitals, City Campus, Nottingham NG5 1PB, UK.
  • 6 Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK.
PMID: 37446144 DOI: 10.3390/ijms241310966
Abstract

The MRE11 nuclease is essential during DNA damage recognition, homologous recombination, and replication. BRCA2 plays important roles during homologous recombination and replication. Here, we show that effecting an MRE11 blockade using a prototypical inhibitor (Mirin) induces synthetic lethality (SL) in BRCA2-deficient ovarian Cancer cells, HeLa cells, and 3D spheroids compared to BRCA2-proficient controls. Increased cytotoxicity was associated with double-strand break accumulation, S-phase cell cycle arrest, and increased Apoptosis. An in silico analysis revealed Mirin docking onto the active site of MRE11. While Mirin sensitises DT40 MRE11+/- cells to the Top1 poison SN-38, it does not sensitise nuclease-dead MRE11 cells to this compound confirming that Mirin specifically inhibits Mre11 nuclease activity. MRE11 knockdown reduced cell viability in BRCA2-deficient PEO1 cells but not in BRCA2-proficient PEO4 cells. In a Mirin-resistant model, we show the downregulation of 53BP1 and DNA repair upregulation, leading to resistance, including in in vivo xenograft models. In a clinical cohort of human ovarian tumours, low levels of BRCA2 expression with high levels of MRE11 co-expression were linked with worse progression-free survival (PFS) (p = 0.005) and overall survival (OS) (p = 0.001). We conclude that MRE11 is an attractive SL target, and the pharmaceutical development of MRE11 inhibitors for precision oncology therapeutics may be of clinical benefit.

Keywords

BRCA2; MRE11; synthetic lethality.

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