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

Abstract

Platinum resistance is a clinical challenge in ovarian cancer. Platinating agents induce DNA damage which activate Mre11 nuclease directed DNA damage signalling and response (DDR). Upregulation of DDR may promote chemotherapy resistance. Here we have comprehensively evaluated Mre11 in epithelial ovarian cancers. In clinical cohort that received platinum- based chemotherapy (n = 331), Mre11 protein overexpression was associated with aggressive phenotype and poor progression free survival (PFS) (p = 0.002). In the ovarian cancer genome atlas (TCGA) cohort (n = 498), Mre11 gene amplification was observed in a subset of serous tumours (5%) which correlated highly with Mre11 mRNA levels (p < 0.0001). Altered Mre11 levels was linked with genome wide alterations that can influence platinum sensitivity. At the transcriptomic level (n = 1259), Mre11 overexpression was associated with poor PFS (p = 0.003). ROC analysis showed an area under the curve (AUC) of 0.642 for response to platinum-based chemotherapy. Pre-clinically, Mre11 depletion by gene knock down or blockade by small molecule inhibitor (Mirin) reversed platinum resistance in ovarian cancer cells and in 3D spheroid models. Importantly, Mre11 inhibition was synthetically lethal in platinum sensitive XRCC1 deficient ovarian cancer cells and 3D-spheroids. Selective cytotoxicity was associated with DNA double strand break (DSB) accumulation, S-phase cell cycle arrest and increased apoptosis. We conclude that pharmaceutical development of Mre11 inhibitors is a viable clinical strategy for platinum sensitization and synthetic lethality in ovarian cancer.

DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities

“…Genomic/Epigenomic Alterations in OC (References) DR MGMT promoter hypermethylation [51,52] MMR Mutations in MLH1, MSH2, MSH6, and PMS2 [53][54][55] MLH1 promoter hypermethylation [56][57][58] NER SNPs in NER genes [59] Homozygous deletions, missense, or splice site mutations in NER genes [60,61] BER SNPs in OGG1, APE1, and XRCC1 [62][63][64][65][66][67][68] APE1 overexpression [69] HR Genetic and epigenetic modifications of genes encoding HR proteins [70][71][72] Mutations in BRCA1, BRCA2, RAD51C, RAD51D and MRN complex genes [70][71][72][73][74][75][76] Downregulation of RAD50 [75,77] RAD51 promoter hypermethylation [60] NHEJ Mutations or overexpression of genes that encoded for NHEJ proteins (DNA-PKs, DNA polymerase Θ, or XRCC4) [60,[78][79][80]] SNPs in NHEJ genes (DNA ligase IV, XRCC1) [60] Chromatin remodelers Mutations in ARID1A [81][82][83][84] Increase sensitivity to DNA-damaging agents (cisplatin, carboplatin, chloroquine) [109][110][111] Panobinostat Rad51…”

The Multiple Faces of the MRN Complex: Roles in Medulloblastoma and Beyond

“…In epithelial ovarian cancer, where a lack of MRN complex protein detection was seen in 41% of the tumors, MRE11 knockdown increased sensitivity towards the PARP inhibitor BMN673 [55]. Moreover, MRE11 inhibition was synthetically lethal in platinum-sensitive XRCC1-deficient ovarian cancer cells and 3D-spheroids [56].…”

“…Possibly due to the roles of the MRN complex in DDR and RSR [75,76], most studies (with one only exception [70]) support the idea that the MRN complex is a critical factor in driving chemo-and radio-resistance. In particular, nuclear accumulation of the MRN complex was associated with chemo-resistance in gastric cancer [77] and ovarian cancer [56,78], and high expression of RAD50 correlates with radio-resistance in colorectal cancer (CRC) patients [79]. Moreover, in pre-clinic ovarian cancer studies, RAD50 expression resulted higher in platinum-resistant cells [80], and platinum treatment increased nuclear sub-cellular localization of NBS1 [78] and RAD50 [80] more in platinum-resistant cells with respect to the sensitive ones, supporting the idea that accumulation of nuclear MRN proteins could contribute to cisplatin resistance in this tumor background.…”

“…In gastric cancer, nuclear accumulation of the MRN proteins was associated with cancer progression, reduced DNA damage, poor prognosis, and chemo-resistance [77]. In ovarian cancer, MRN gene or protein overexpression was more frequently found in high-grade tumors [55,132], significantly associated with platinum resistance, shorter progression-free survival (PFS), and poor overall survival (OS) [56,78,80], and was an independent prognostic factor for recurrence [133]. In uveal melanoma NBS1 expression strongly correlated with tumor severity and metastatic death and it was proposed to use a high expression of NBS1 at the time of diagnosis of the primary eye tumor to select those patients who are at high risk of metastasis, in order to treat them prophylactically with adjuvant systemic therapy [134].…”

Evolving DNA repair synthetic lethality targets in cancer

“…Loss of XRCC1 has been shown to correlate with more aggressive cancers and worse prognosis. Intriguingly, PARP, ATM, ATR, WEE1, Mre11, and DNA-PKcs inhibitors have all been found to be synthetically lethal to XRCC1-deficient cells, highlighting a novel therapeutic avenue in these aggressive tumors [121][122][123][124].…”