Oncotarget

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Mdm2 inhibition confers protection of p53-proficient cells from the cytotoxic effects of Wee1 inhibitors

Yizhu Li, Priyanka Saini, Anusha Sriraman and Matthias Dobbelstein _

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Oncotarget. 2015; 6:32339-32352. https://doi.org/10.18632/oncotarget.5891

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Abstract

Yizhu Li1,*, Priyanka Saini1,*, Anusha Sriraman1,* and Matthias Dobbelstein1

1 Institute of Molecular Oncology, Göttingen Centre of Molecular Biosciences (GZMB), Faculty of Medicine, University of Göttingen, Göttingen, Germany

* These authors are equal first authors

Correspondence to:

Matthias Dobbelstein, email:

Keywords: Wee1, Mdm2, p53, gemcitabine, premature mitosis

Received: June 04, 2015 Accepted: September 20, 2015 Published: September 29, 2015

Abstract

Pharmacological inhibition of the cell cycle regulatory kinase Wee1 represents a promising strategy to eliminate cancer cells. Wee1 inhibitors cooperate with chemotherapeutics, e. g. nucleoside analogues, pushing malignant cells from S phase towards premature mitosis and death. However, considerable toxicities are observed in preclinical and clinical trials. A high proportion of tumor cells can be distinguished from all other cells of a patient’s body by inactivating mutations in the tumor suppressor p53. Here we set out to develop an approach for the selective protection of p53-proficient cells against the cytotoxic effects of Wee1 inhibitors. We pretreated such cells with Nutlin-3a, a prototype inhibitor of the p53-antagonist Mdm2. The resulting transient cell cycle arrest effectively increased the survival of cells that were subsequently treated with combinations of the Wee1 inhibitor MK-1775 and/or the nucleoside analogue gemcitabine. In this constellation, Nutlin-3a reduced caspase activation and diminished the phosphorylation of Histone 2AX, an indicator of the DNA damage response. Both effects were strictly dependent on the presence of p53. Moreover, Nutlin pre-treatment reduced the fraction of cells that were undergoing premature mitosis in response to Wee1 inhibition. We conclude that the pre-activation of p53 through Mdm2 antagonists serves as a viable option to selectively protect p53-proficient cells against the cytotoxic effects of Wee1 inhibitors, especially when combined with a nucleoside analogue. Thus, Mdm2 antagonists might prove useful to avoid unwanted side effects of Wee1 inhibitors. On the other hand, when a tumor contains wild type p53, care should be taken not to induce its activity before applying Wee1 inhibitors.


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