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BMC Cancer. 2019 Jan 10;19(1):44. doi: 10.1186/s12885-018-5250-4.

Sequential therapeutic targeting of ovarian Cancer harboring dysfunctional BRCA1.

Author information

1
Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada.
2
Department of Experimental Surgery, McGill University, Montreal, QC, Canada.
3
Division of Gynecologic Oncology, Jewish General Hospital, McGill University, 3755 Cote Ste. Catherine Road, Montreal, QC, H3T 1E2, Canada.
4
Division of Gynecologic Oncology, Jewish General Hospital, McGill University, 3755 Cote Ste. Catherine Road, Montreal, QC, H3T 1E2, Canada. amber.yasmeen@mail.mcgill.ca.
5
Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada. amber.yasmeen@mail.mcgill.ca.
6
Department of Experimental Medicine, McGill University, Montreal, QC, Canada.

Abstract

BACKGROUND:

Poly (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.

METHODS:

BRCA1-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.

RESULTS:

Exposure 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.

CONCLUSION:

Pre-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.

KEYWORDS:

BRCA1/2; Chemoresistance; DNA repair pathway; Ovarian Cancer; PARP inhibitor; Synthetic lethality

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