Targeting Mre11 overcomes platinum resistance and induces synthetic lethality in XRCC1 deficient epithelial ovarian...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Platinum resistance is a major clinical hurdle in ovarian cancer treatment.
• Platinum agents trigger DNA damage response (DDR) pathways, potentially leading to chemotherapy resistance.
• Mre11 nuclease plays a key role in DNA damage signaling and response.

Purpose of the Study:

• To comprehensively evaluate the role of Mre11 in epithelial ovarian cancers.
• To investigate the association between Mre11 levels and platinum resistance.
• To explore Mre11 inhibition as a therapeutic strategy for ovarian cancer.

Main Methods:

• Analysis of Mre11 protein and gene expression in clinical ovarian cancer cohorts (n=331 and n=498).
• Transcriptomic analysis (n=1259) to correlate Mre11 levels with progression-free survival (PFS).
• Pre-clinical studies using gene knockdown and small molecule inhibitors (Mirin) in ovarian cancer cell lines and 3D spheroids.

Main Results:

• Mre11 overexpression was linked to aggressive phenotype and poor PFS in patients receiving platinum chemotherapy (p=0.002).
• Mre11 gene amplification (5% of serous tumors) correlated with elevated mRNA levels and genome-wide alterations affecting platinum sensitivity.
• Mre11 inhibition reversed platinum resistance, induced synthetic lethality in XRCC1-deficient cells, and led to DNA double-strand breaks, cell cycle arrest, and apoptosis.

Conclusions:

• Mre11 is a potential biomarker for aggressive ovarian cancer and poor response to platinum chemotherapy.
• Targeting Mre11 with inhibitors represents a promising clinical strategy for platinum sensitization.
• Mre11 inhibition may exploit synthetic lethality for targeted ovarian cancer therapy, particularly in platinum-resistant or XRCC1-deficient cases.