Abstract 3337: Modulating the APE1/NPM1 interaction in cancer.

Abstract

Abstract DNA repair pathways protect the genome from endogenous and environmental DNA damage. Such defensive mechanisms, however, enable tumor cells to survive DNA damage caused by chemo- and radio-therapy. Moreover, alterations of DNA repair pathways that may occur during tumorigenesis can make cancer cells reliant on a subset of repair enzymes for survival. Hence, knowledge of the mechanisms involved in the control of DNA repair proteins is of great interest for cancer diagnosis and treatment. The Apurinic/apyrimidinc endonuclease 1 (APE1) is an essential protein in eukaryotic cells. As the main AP-endonuclease in mammals, this protein is central to the base excision DNA repair pathway (BER). Beside its role in the maintenance of genomic stability, APE1 modulates gene expression by tuning the redox status of several transcription factors. Moreover, recent reports suggest that APE1 may take part in RNA processing and degradation, thus controlling the transcriptional output of the cell. Overexpression and aberrant localization of APE1 are recurrent phenotypes in tumors. Both situations are prognostic indicators of aggressiveness and onset of resistance. Interestingly, downregulation or inhibition of APE1 sensitizes cells to pharmacologically relevant gentoxins. We identified and characterized the molecular association between APE1 and Nucleophosmin (NPM1), a multifunctional protein involved in the preservation of genome stability, rRNA maturation and chromatin remodeling. The association with NPM1 modulates subcellular localization and endonuclease activity of APE1. Accordingly, NPM1−/− cells show lower BER capacity, and expression of an APE1 mutant unable to interact with NPM1 severely impairs cell proliferation. We recently reported a correlation between APE1 and NPM1 expression levels in ovarian cancer, along with a poorer prognosis for patients having higher NPM1 levels. These observations suggest that tumors that display an augmented APE1/NPM1 association may exhibit increased aggressiveness and resistance. Targeting the APE1/NPM1 interaction therefore represents a novel strategy for the development of anticancer drugs, as tumor cells which rely on higher levels of APE1 and NPM1 for proliferation and survival may be more sensitive than normal cells. We exploited the AlphaScreen technology to screen for small molecules that act as inhibitors of the APE1/NPM1 interaction. Our approach detected a set of compounds able to interfere with the APE1/NPM1 association in vivo. Interestingly, some of these molecules display anti-proliferative activity and sensitize cells to genotoxins. To the best of our knowledge, this is the first attempt to target the APE1 interactome. Given the prognostic significance of the APE1 and NPM1 overexpression, these compounds might prove particularly effective in the treatment of tumors that show abundant levels of both proteins, such as ovarian or hepatic carcinomas. Citation Format: Mattia Poletto, Dorjbal Dorjsuren, Lisa Lirussi, Carlo Vascotto, Pasqualina L. Scognamiglio, Daniela Marasco, Ajit Jadhav, David J. Maloney, Anton Simeonov, David M. Wilson, Gianluca Tell. Modulating the APE1/NPM1 interaction in cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3337. doi:10.1158/1538-7445.AM2013-3337