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Abstract
BackgroundPoly (ADP-ribose) polymerase inhibitors (PARPi) have become the first targeted therapies available in the treatment of patients with high-grade serous ovarian cancer (HGSOC). We recently described a significant reduction in PARP1 protein levels in vitro and in vivo in patients treated with standard carboplatinum-paclitaxel chemotherapy, raising the question whether the sequence of treatment used today with chemotherapy followed by PARPi is optimal. In this study, we aim to evaluate if the sequence of PARPi followed by chemotherapy could be more beneficial.MethodsBRCA1-mutated (UWB1.287, SNU-251), epigenetically-silenced (OVCAR8), and wild-type (SKOV3, A2780PAR & A2780CR) ovarian cancer cell lines were exposed to clinically relevant doses of PARPi followed by different doses of standard chemotherapy and compared to the inverse treatment. The therapeutic efficacy was assessed using colony formation assays. Flow cytometry was used to evaluate cell apoptosis rate and the changes in cell cycle. Finally, apoptotic and cell cycle protein expression was immunodetected using western blot.ResultsExposure to PARPi prior to standard chemotherapy sensitized BRCA1-mutated or epigenetically-silenced BRCA1 cell lines to lower doses of chemotherapy. Similar results were observed in BRCA1 wild-type and cell lines in which BRCA1 functionality was restored. Moreover, this treatment increased the apoptotic rate in these cell lines.ConclusionPre-treatment with PARPi followed by standard chemotherapy in vitro is more efficient in growth inhibition and induction of apoptosis compared to the administration of standard chemotherapy followed by PARPi.
Highlights
(ADP-ribose) polymerase inhibitors (PARPi) have become the first targeted therapies available in the treatment of patients with high-grade serous ovarian cancer (HGSOC)
As a combined effect of Poly (ADP-ribose) polymerase inhibitors (PARPi) follow chemotherapy has greater synergism in BRCA1 silenced cells and to a lesser degree in BRCA1 wild-type cells, which provide a therapeutic option for HGSOC patients independent of their BRCA1 status
We have indicated a new direction of employing PARPi as a first line of treatment, suggesting that pre-treatment with PARPi follow chemotherapy as frontline therapy might yield significantly better outcome in HGSOC, and could be explored in other patients with homologous recombinationdeficient cancers
Summary
(ADP-ribose) polymerase inhibitors (PARPi) have become the first targeted therapies available in the treatment of patients with high-grade serous ovarian cancer (HGSOC). High-Grade Serous Ovarian Cancer (HGSOC) is the most common subtype (70%) [3] and the majority show a significant, but transient response to platinum-taxane therapy and debulking surgery. A significant proportion of HGSOC contain mutations in genes involved in the homologous recombination pathway of DNA repair (HR), especially BRCA1 and BRCA2. Both BRCA1/2 mutation-associated tumors and tumors with HR deficiencies have higher response rates to platinum-based chemotherapy [6, 7]. The majority of HGSOC are initially sensitive to platinum-based chemotherapy, up to 75% of responding patients will relapse and developed platinum-resistance disease resulting in poor 5-year survival [8, 9]. The response rates and disease-free intervals will decrease, developing drug resistance
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