TY - JOUR

T1 - Selective Killing of BRCA2-Deficient Ovarian Cancer Cells via MRE11 Blockade

AU - Alblihy , Adel

AU - Ali , Reem

AU - Algethami, Mashael

AU - Ritchie, Alison A.

AU - Shoqafi, Ahmed

AU - Alqahtani, Shatha

AU - Mesquita, Katia A.

AU - Toss, Michael S.

AU - Ordóñez-Morán , Paloma

AU - Jeyapalan, Jennie N.

AU - Dekker , Lodewijk

AU - Salerno, Martina

AU - Hartsuiker, Edgar

AU - Grabowska , Anna M.

AU - Rakha, Emad A.

AU - Mongan, Nigel P.

AU - Madhusudan, Srinivasan

PY - 2023/6/30

Y1 - 2023/6/30

N2 - 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.

AB - 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.

KW - BRCA2

KW - BRCA2 Protein - metabolism

KW - Cell Line, Tumor

KW - DNA Repair

KW - DNA-Binding Proteins - metabolism

KW - Female

KW - HeLa Cells

KW - Humans

KW - MRE11

KW - MRE11 Homologue Protein - genetics - metabolism

KW - Ovarian Neoplasms - drug therapy - genetics

KW - Precision Medicine

KW - synthetic lethality

U2 - 10.3390/ijms241310966

DO - 10.3390/ijms241310966

M3 - Article

VL - 24

JO - International journal of molecular sciences

JF - International journal of molecular sciences

SN - 1422-0067

IS - 13

ER -