Effect of MRE11 Loss on PARP-Inhibitor Sensitivity in Endometrial Cancer In Vitro

Abstract

Aim of the studyTo evaluate the frequency of MRE11/RAD50/NBS1 (MRN)-complex loss of protein expression in endometrial cancers (EC) and to determine whether loss of MRE11 renders the cancer cells sensitive to Poly(ADP-ribose) polymerase (PARP)-inhibitory treatment.MethodsMRN expression was examined in 521 samples of endometrial carcinomas and in 10 cancer cell lines. A putative mutation hotspot in the form of an intronic poly(T) allele in MRE11 was sequenced in selected cases (n = 26). Sensitivity to the PARP-inhibitor, BMN673 was tested in colony formation assays before and after MRE11 silencing using siRNA. Homologous recombination (HR) DNA repair was evaluated by RAD51-foci formation assay upon irradiation and drug treatment.ResultsLoss of MRE11 protein was found in 30.7% of EC tumours and significantly associated with loss of RAD50, NBS1 and mismatch repair protein expression. One endometrial cell line showed a markedly reduced MRE11 expression due to a homozygous poly(T) mutation of MRE11, thereby exhibiting an increased sensitivity to BMN673. MRE11 depletion sensitizes MRE11 expressing EC cell lines to the treatment with BMN673. The increased sensitivity to PARP-inhibition correlates with reduced RAD51 foci formation upon ionizing radiation in MRE11-depleted cells.ConclusionLoss of the MRE11 protein predicts sensitivity to PARP-inhibitor sensitivity in vitro, defining it as an additional synthetic lethal gene with PARP. The high incidence of MRE11 loss in ECs can be potentially exploited for PARP-inhibitor therapy. Furthermore, MRE11 protein expression using immunohistochemistry could be investigated as a predictive biomarker for PARP-inhibitor treatment.

Next-Generation Sequencing Reveals a Nonsense Mutation (p.Arg364Ter) in MRE11A Gene in an Indian Patient with Familial Breast Cancer

“…The proband's mother died at 77 years of endometrial cancer. This case and other studies highlight the association of mutations in the MRE11A gene with endometrial cancer [22][23][24]. Koppensteiner et al [23] demonstrated that endometrial cancer associated with MRE11 mutation has higher sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitor therapy.…”

“…This case and other studies highlight the association of mutations in the MRE11A gene with endometrial cancer [22][23][24]. Koppensteiner et al [23] demonstrated that endometrial cancer associated with MRE11 mutation has higher sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitor therapy. PARP inhibitors are effective against tumors with deficient DNA repair mechanisms, and recent reports provide evidence that MRE11 mutations can serve as a predictive biomarker for the efficacy of PARP inhibitors.…”

The role of poly(ADP-ribose) polymerase inhibitors in the treatment of endometrial cancer: a scoping review of the current literature

“…Of the studies selected for analysis, 4 were in vitro [14,[32][33][34], 2 were in vivo [35,36], 6 were reviews [3,7,[37][38][39][40], and 5 were clinical trials.…”

“…Koppensteiner et al sought to determine if loss of MRE11 would result in increased sensitivity to a PARP-inhibitor [33]. Among endometrial cancers tested, nearly one third lacked MRE11 staining.…”

A New Approach in Cancer Treatment: Poly(ADP-Ribose) Polymerase-1 Inhibitors

“…PARP inhibisyonu hücrelerde apoptozis ya da yaşlanmaya neden olur (42). Olaparib ile yapılan çalışmalarda over ve endometriyum kanserlerinde önemli yarar sağlanmıştır (43).…”