MRE11-RAD50-NBS1 COMPLEX BLOCKADE TO REVERSE PLATINUM RESISTANCE AND INDUCE SYNTHETIC LETHALITY IN EPITHELIAL OVARIAN CANCERS

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Resistance to platinum drugs (carboplatin, cisplatin) negatively impacts patients’ outcomes in ovarian cancer. Platinum-based chemotherapy cause intra-strand and inter-strand DNA adducts, which contribute to DSBs during replication. Proficient DNA repair is a critical mechanism that leads to resistance to platinating agents. Targeting DNA repair proteins is a promising strategy for ovarian cancer personalization therapy. The MRE11-RAD50-NBS1 (MRN) complex is a ‘first responder’ to DNA damage and is critical for repair of double strand breaks (DSBs) and stalled replication forks. Here we show that MRE11, RAD50 and NBS1 overexpression at the transcriptional and protein level is linked to poor survival outcomes in ovarian cancer patients treated with platinum chemotherapy. Pre-clinically, MRE11, RAD50 and NBS1 depletion promoted platinum sensitivity in ovarian resistance cell lines. Increased sensitivity was associated with accumulation of DSBs, cell cycle arrest and apoptosis. Mirin, a small molecular inhibitor of the 3′ to 5′ exonuclease activity of MRE11 was increased platinum sensitivity in ovarian resistance cell lines, was correlated with increased DSB accumulation, cell cycle arrest and apoptotic cells. Mirin was also synthetically lethal in BRCA2-deficient or XRCC1-deficient ovarian cancer cells including in 3D-spheroid models as evidenced by DSB accumulation, cell cycle arrest and increased apoptotic We generated a mirin resistant BRCA2-deficient PEO1R cell line which is cross-resistant to cisplatin and Olaparib (PARP inhibitor) including 3D-spheroid models. PEO1R cells have not restored BRCA2 protein expression but inactivated 53BP1 and activated DSB repair through upregulation of MRE11 and other components of HR, NER and MMR pathways at mRNA and protein levels. Interestingly, PEO1R cells also overexpressed OCT4 transcription factor which physically interacted with MRE11 promoting an aggressive cancer stem cell-like phenotype (characterised by overexpression of CD44, OCT4 & ZEB1), increased proliferation, spheroid formation, invasion, epithelial-to-mesenchymal transition (EMT), enhanced DNA repair expression and reduced apoptosis and increased tumorigenicity in mice xenograft models. We conclude that MRE11, RAD50 and NBS1 are key predictive biomarkers in ovarian cancer, MRE11 is involved in cancer stem cell regulation and MRE11 targeting may be suitable for clinical application in DNA repair deficient ovarian cancers.

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