Oncotarget

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This article has been corrected. Correction in: Oncotarget. 2024; 15:142-142.

Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer

Maryam Zanjirband, Nicola Curtin, Richard J. Edmondson and John Lunec _

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Oncotarget. 2017; 8:69779-69796. https://doi.org/10.18632/oncotarget.19266

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Abstract

Maryam Zanjirband1, Nicola Curtin1, Richard J. Edmondson2 and John Lunec1

1Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE2 4HH, United Kingdom

2Faculty Institute for Cancer Sciences, University of Manchester, Manchester M13 9WL, United Kingdom

Correspondence to:

John Lunec, email: [email protected]

Keywords: ovarian cancer, targeted therapy, rucaparib, Nutlin-3/RG7388, combined treatment

Received: March 15, 2017     Accepted: June 10, 2017     Published: July 15, 2017

ABSTRACT

Ovarian cancer is the seventh most common cancer worldwide for females and the most lethal of all gynecological malignancies. The treatment of ovarian cancer remains a challenge in spite of advances in debulking surgery and changes in both chemotherapy schedules and routes of administration. Cancer treatment has recently been improving with the introduction of targeted therapies to achieve greater specificity and less cytotoxicity. Both PARP inhibitors and MDM2-p53 binding antagonists are targeted therapeutic agents entered into clinical trials. This preclinical study evaluated the effect of Nutlin-3/RG7388 and rucaparib as single agents and in combination together in a panel of ovarian cancer cell lines. Median-drug-effect analysis showed Nutlin-3/RG7388 combination with rucaparib was additive to, or synergistic in a cell type-dependent manner. Mechanism studies showed rucaparib alone had no effect on p53 stabilization or activity. Although treatment with Nutlin-3 or RG7388 induced stabilization of p53 and upregulation of p21WAF1 and MDM2, the addition of rucaparib did not enhance the p53 activation seen with the MDM2 inhibitors alone. These results demonstrate that the synergistic effect on growth inhibition observed in the combination between rucaparib and Nutlin-3/RG7388 is not the result of increased p53 molecular pathway activation. Nevertheless, combined treatment of Nutlin-3/RG7388 with rucaparib increased cell cycle arrest and apoptosis, which was marked for A2780 and IGROV-1. These data indicate that combination treatment with MDM2 inhibitors and rucaparib has synergistic and dose reduction potential for the treatment of ovarian cancer, dependent on cell type.


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