Abstract 5204: Targeting OGG1 arrest cancer cell proliferationby mitochondrial dysfunction and replication stress

Altered oncogene expression in cancer cells causes lost redox homeostasis resulting in oxidative DNA damage, e.g., 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER, and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstruct A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause lost mitochondrial function leading to S-phase damage, replication stress and lost proliferation or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g., PARP1, as potential targets for treatment of cancer. Citation Format: Carlos Benitez-Buelga, Torkild Visnes, Kumar Sanjiv, Oliver Mortusewicz, Ulrika Warpman Berglund, Thomas Helleday. Targeting OGG1 arrest cancer cell proliferationby mitochondrial dysfunction and replication stress [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5204.