Journal of Cancer Research and Immuno-Oncology
Open Access
ISSN: 2684-1266
ISSN: 2684-1266
Adel Alblihy
King Fahd Security College, Saudi Arabia
Scientific Tracks Abstracts: J Cancer Res Immunooncol
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 silicon analysis revealed Mirin docking onto the active site of MRE11. While Mirin sensitizes 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 tumors, 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.
Dr. Adel Alblihy is an academic oncologist, his research focus on the evaluation of DNA damage signaling and repair in cancer. We identified with Prof. Madhusudan several novel DNA repair biomarkers, potential drug target and new strategies for personalized treatment approaches targeting DNA repair in cancer. I published several papers in Targeting DNA repair for caner personalized therapy.