Combination of triapine, olaparib, and cediranib suppresses progression of BRCA-wild type and PARP inhibitor-resistant epithelial ovarian cancer

Abstract

PARP inhibitors target BRCA mutations and defective homologous recombination repair (HRR) for the treatment of epithelial ovarian cancer (EOC). However, the treatment of HRR-proficient EOC with PARP inhibitors remains challenging. The objective of this study was to determine whether the combination of triapine (ribonucleotide reductase inhibitor), cediranib (vascular endothelial growth factor receptor tyrosine kinase inhibitor), and the PARP inhibitor olaparib synergized against BRCA wild-type and HRR-proficient EOC in xenograft mouse models. In addition, the mechanisms by which cediranib augmented the efficacy of triapine and olaparib were investigated. BRCA-wild type and PARP inhibitor-resistant EOC cell lines were implanted subcutaneously (s.c.) into nude mice or injected intraperitoneally (i.p.) into SCID-Beige mice. Mice were then treated i.p. with olaparib, cediranib, triapine, various double and triple combinations. The volume of s.c tumor in nude mice and the abdominal circumference of SCID-Beige mice were measured to evaluate the effectiveness of the treatment to delay tumor growth and prolong the survival time of mice. In both xenograft mouse models, the combination of triapine, olaparib and cediranib resulted in marked suppression of BRCA-wild type EOC growth and significant prolongation of the survival time of mice, with efficacy greater than any double combinations and single drugs. Furthermore, we identified that cediranib abrogated pro-survival and anti-apoptotic AKT signaling, thereby enhancing the efficacy of triapine and olaparib against BRCA-wild type EOC cells. Taken together, our results demonstrate a proof-of-principle approach and the combination regiment holds promise in treating BRCA-wild type and PARP inhibitor-resistant EOC.

In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer

“…We have previously demonstrated that both PEO4ip and SKOV3 cells are BRCA-wild type and olaparib-resistant in cell-based assays and in vivo 29 , 30 , 38 . We first evaluated the efficacy of the combination of DB4 and olaparib to treat PEO4ip tumor xenografts, as determined by the median survival time, in a peritoneal mouse model 38 . Mice were implanted intraperitoneally (i.p.)…”

“…We ascertain the efficacy of the combination of DB4 and olaparib to treat SKOV3 tumor xenografts, as determined by the tumor size, in a subcutaneous (s.c.) mouse model 30 , 38 . Mice were implanted s.c. with SKOV3 cells and then treated i.p.…”

“…The assay was performed as described previously 38 . At the end of 24 h drug treatment, cells were lysed with the lysis buffer (PBS, 1% NP40, 0.1% SDS).…”

“…We have also substantiated that depletion of the R2 subunit of RNR by siRNA suppresses the repair of endonuclease-induced DSBs by HR 29 , 30 . Furthermore, we have shown that the combination of triapine, olaparib, and cediranib effectively curbs subcutaneous growth and peritoneal progression of BRCA-wild type EOC xenografts and extends the survival time of mice 38 . Cediranib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases included in the combination to enhance the efficacy of olaparib and triapine.…”

H2A Histone Family Member X (H2AX) Is Upregulated in Ovarian Cancer and Demonstrates Utility as a Prognostic Biomarker in Terms of Overall Survival

“…The intriguing rise in H2AX 24 h after H2O2 application in SKOV3 cells suggests that this line may exhibit a type of 'BRCAness'. This refers to EOC (up to 50% of HGS) that exhibit a defective phenotype of homologous recombination repair (HRR) without BRCA mutations [34,35]. Of note, SKOV3 has 3 other genes mutated involved in HRR [36].…”