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Targeting OGG1 arrests cancer cell proliferation by inducing replication stress
Bishoy M. F. Hanna 1 , Torkild Visnes 1, 2 , Carlos Benitez-Buelga 1 , Armando Cazares-Körner 1 , Kumar Sanjiv 1 , Oliver Mortusewicz 1 , Geoffrey Masuyer 3, 4 , Olov Wallner 1 , Maurice Michel 1 , Olga Loseva 1 , Ann-Sofie Jemth 1 , Christina Kalderen 1 , Pal Stenmark 3, 5 , Ulrika Warpman Berglund 1 , Thomas Helleday * 1, 6
1  Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden
2  Department of Biotechnology and Nanomedicine, SINTEF Industry, N-7465 Trondheim, Norway
3  Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden
4  Department of Pharmacy and Pharmacology, Centre for Therapeutic Innovation. University of Bath, Bath BA2 7AY, UK
5  Department of Experimental Medical Science, Lund University, SE-221 00 Lund, Sweden
6  Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK


Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG). 8-oxoguanine-DNA glycosylase (OGG1) is the main glycosylase responsible for the recognition and excision of 8-oxoG to initiate base excision repair (BER). Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs 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 developed TH5487, a potent small-molecule inhibitor that targets OGG1's active site. We show that TH5487 suppresses the growth of a wide range of cancer cells, with a favourable therapeutic index compared to non‑transformed cells. Mechanistically, TH5487 treatment results in accumulation of genomic 8-oxoG lesions, alters OGG1-chromatin dynamics and impairs OGG1 recruitment to DNA damage regions. Furthermore, OGG1 inhibition with TH5487 induces replication stress and proliferation arrest representing a novel mechanistic approach to target cancer. This study validates OGG1 as a potential target for cancer treatment.

Keywords: DNA damage response; oxidative DNA damage; base excision repair; OGG1 glycosylase; OGG1 inhibitor; TH5487; cancer; replication stress