Abstract 2970: Interference with DNA repair through inhibition of Wee1

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Abstract In response to DNA damage, the so-called ‘DNA damage response’ provokes a cell cycle arrest to facilitate DNA repair. Recently, it has become clear that cells can respond to DNA damage throughout the cell cycle, except during mitosis. Specifically, the mitotic kinases Cdk1 and Plk1 were shown to be responsible for the inactivation of key DNA damage checkpoint proteins, including Claspin and 53BP1. Here we have addressed the possibilities to exploit the mitotic inactivation of the DNA damage response with the purpose to block proper cellular responses to DNA damage during interphase. We hypothesized that mimicking the ‘mitotic’ state of the DNA damage response could potentially inhibit DNA repair and could sensitize cancer cells to genotoxic therapy. To this end, we employed chemical inhibition of the Wee1 kinase. Wee1 is known to prevent unscheduled Cdk1 activation and inhibition of Wee1 has previously been shown to provoke Cdk1 activity. We could show that chemical Wee1 inhibition indeed leads to upregulation of Cdk1 activity. Importantly, we furthermore showed that recruitment of critical repair factors, such as BRCA1 were no longer recruited to sites of DNA damage. Furthermore, we show that DNA repair kinetics were decreased after inhibition of Wee1. Finally, we could show that inhibition of Wee1 sensitized cells to genotoxic chemotheapeutics and irradiation. Thus, forced activation of mitotic kinase interferes with normal DNA damage responses and can be used for radio/chemosensitization. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2970. doi:10.1158/1538-7445.AM2011-2970