Abstract 4171: The role of ATM and 53BP1 as predictive markers and therapeutic targets in advanced stage cervical cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 8_Supplement; p. 4171
• Main Authors: Roossink, Frank, Wieringa, Hylke W., Noordhuis, Maartje G., Kok, Mirjam, ten Hoor, Klaske A., de Bock, Geertruida H., de Jong, Steven, van der Zee, Ate G. J., Schuuring, Ed M.D., Wisman, G. Bea A., van Vugt, Marcel A.T.M.
• Format: Journal Article
• Language: English
• Published: 15.04.2011
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2011-4171

Abstract Chemoradiation is the standard of care for advanced stage cervical cancer patients and induces cytotoxicity by inducing high levels of DNA breaks in the tumor. The ability of tumor cells to repair therapy-induced DNA damage may counteract the effects of chemoradiation. The pathway responsible for DNA double strand break repair is called the ‘DNA damage response’. In vitro we observed robust radiation-induced G1 and G2 cell cycle arrests in cervical cancer cell lines, despite the expression of HPV oncogenes, which impact the DNA damage response through rapid p53 degradation. Moreover, the DNA damage checkpoint protein ATM and its substrate 53BP1 are required for proper induction of cell cycle checkpoint arrests. Yet, when long-term survival effects were measured, inhibition of ATM, but not 53BP1, strongly sensitized cervical cancer cells to irradiation. To validate the putative role of ATM and 53BP1 in advanced stage cervical cancer we investigated presence and activity of ATM as well as 53BP1 in relation to response-to-treatment in a large, well documented, series of advanced stage cervical cancer patients (n=375). We found that high levels of ATM were related to poor response to chemoradiation (P=0.013). Importantly, high phosho-ATM immunostaining, reflecting active ATM, predicted poor responses to chemoradiation even better (P=0.004). In addition, high phospho-ATM levels predicted shorter disease-specific survival (P=0.020). Although presence of phosphorylated 53BP1 did relate to phospho-ATM (P=0.001), it was not significantly related to any clinicopathological features or survival. Combined, our data suggest the prognostic value of ATM signaling for responses to chemoradiation and point at ATM inhibition as a potential therapeutic target to increase treatment efficacy in advanced stage cervical cancers. Acknowledgements This research is supported by the Dutch Cancer Society (RUG 2007-3719) and the Netherlands Organization for Scientific Research (NWO-VENI 916.76.062). 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 4171. doi:10.1158/1538-7445.AM2011-4171