Chemoresistance poses one of the most significant challenges of cancer therapy. Carboplatin (CbPt) is one of the most used chemotherapeutics in ovarian cancer (OVC) treatment. MRE11 constitutes a part of homologous recombination (HR), which is responsible for the repair of CbPt-induced DNA damage, particularly DNA crosslinks. The study's main aim was to address the role of HR in CbPt chemoresistance in OVC and to evaluate the possibility of overcoming CbPt chemoresistance by Mirin-mediated MRE11 inhibition in an OVC cell line. Lower expression of MRE11 was associated with better overall survival in a cohort of OVC patients treated with platinum drugs (TCGA dataset, P < 0.05). Using in vitro analyses, we showed that the high expression of HR genes drives the CbPt chemoresistance in our CbPt-resistant cell line model. Moreover, the HR inhibition by Mirin not only increased sensitivity to carboplatin (P < 0.05) but also rescued the sensitivity in the CbPt-resistant model (P < 0.05). Our results suggest that MRE11 inhibition with Mirin may represent a promising way to overcome OVC resistance. More therapy options will ultimately lead to better personalized cancer therapy and improvement of patients' survival.

1st Faculty of Medicine Charles University 121 08 Prague Czech Republic

3rd Faculty of Medicine Charles University 100 00 Prague Czech Republic

Biomedical Center Faculty of Medicine in Pilsen Charles University 323 00 Pilsen Czech Republic

Department of Molecular Biology of Cancer Institute of Experimental Medicine Czech Academy of Sciences 142 20 Prague Czech Republic

Faculty of Science Charles University 128 00 Prague Czech Republic

Toxicogenomics Unit National Institute of Public Health 100 00 Prague Czech Republic

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Commentary: Special Issue: Current Understanding of Colorectal and Pancreatic Cancers