BRCA Status Does Not Predict Synergism of a Carboplatin and Olaparib Combination in High-Grade Serous Ovarian Cancer Cell Lines

Abstract

Over 50% of epithelial ovarian cancers express the BRCAness profile that leads to a dysfunctional homologous recombination repair system. The combination of a dysfunctional homologous recombination repair system and a poly(ADP-ribose) polymerase (PARP) inhibitor results in a synthetic lethal phenotype. The PARP inhibitor olaparib, approved as a monotherapy for patients with a germline BRCA mutation, has shown promising results in preclinical studies when combined with DNA damaging agents, such as carboplatin. However, dose-limiting toxicities have hindered the use of a combination therapy with olaparib in the clinical setting. By concurrent administration of carboplatin and olaparib at various molar ratios of drugs, the aim of this study was to explore the optimal dosing ratio of carboplatin-olaparib combinations in a comprehensive panel of eight BRCA-proficient and -deficient high-grade serous ovarian cancer (HGSOC) cell lines. Overall, synergy was observed in the BRCA1/2-mutated or defective cell lines when olaparib was combined at lower molar ratios of olaparib to carboplatin. Immunostaining of γH2AX foci revealed increased DNA damage as a result of this synergistic drug combination in the UWB1.289 paired cell lines. In vitro activity of the individual agents, carboplatin and olaparib, did not correlate with PARP1 expression in each cell line. Importantly, synergism was also observed in a subset of BRCA wild-type cell lines (OV90 and PEO4) suggesting therapeutic benefits of this combination beyond BRCA-dependent synthetic lethality. The administration of drugs at synergistic ratios has the potential to increase efficacy and reduce toxicity.

Sequential therapeutic targeting of ovarian Cancer harboring dysfunctional BRCA1

“…PARPi is currently indicated as maintenance treatment for recurrent HGSOC following second line platinum-based therapy [39]. Previously, we reported that PARP1 protein levels were reduced following chemotherapy in vitro and in vivo [28].…”

Combining PARP Inhibition with Platinum, Ruthenium or Gold Complexes for Cancer Therapy

“…Another notable example includes a study on the combination of carboplatin and olaparib conducted in high-grade serous ovarian cancer cells (HGSOC). [119] Synergy was observed in both BRCA1/2-proficient and -deficient cell lines, indicating that the therapeutic benefits of this combination is independent of BRCA status (Figure 8a). Mechanistic studies revealed that the synergy observed in BRCA-deficient UWB1.289 cell lines were due to increased DNA DSBs (Figure 8b).…”

“…Western blotting and immunofluorescence studies indicated that this combination exerted its cytotoxicity via DNA damage, enhancing NHEJ repair while inhibiting HR repair. Another notable example includes a study on the combination of carboplatin and olaparib conducted in high‐grade serous ovarian cancer cells (HGSOC) [119] . Synergy was observed in both BRCA1/2‐proficient and ‐deficient cell lines, indicating that the therapeutic benefits of this combination is independent of BRCA status (Figure 8a).…”

Phase I/Ib study of olaparib and carboplatin in heavily pretreated recurrent high-grade serous ovarian cancer at low genetic risk

“…Concomitant use of PARPi with a platinum agent has been tested in several types of cancer, demonstrating increased cytotoxicity [31–35]. PARP inhibition potentiated platinum cytotoxicity in the O-342/DDP and CH1cisR platinum-resistant ovarian cancer cell lines [31, 32], as well as in the BRCA wt and BRCA 2-restored OV90 and PEO4 ovarian cancer cell lines, respectively [33]. The PARPi CEP-6800 and olaparib also enhanced platinum-induced cytotoxicity in HRR - proficient non-small cell lung and colorectal carcinomas, respectively [34, 35].…”