Abstract ES12-2: Targeted DNA repair in cancer and new NUDT5 inhibitors to block hormone signalling to target breast cancer

Abstract

Abstract DNA damaging agents, i.e., radio- and chemotherapy, constitute the backbone for treatment of a wide variety of cancers and may result in complete cure from the disease. Our strategy is to exploit endogenous DNA damage caused by cancer vulnerabilities, by DNA repair inhibitors using a synthetic lethal strategy. Our early work on PARP inhibitors in BRCA mutated cancers is establishing in breast cancer and here I will describe novel DNA repair targets and how these can be integrated into treatment of breast cancer. Here, I will also describe a novel link between PARP and hormone dependent cancers. Interestingly, we show that the PARP related protein NUDT5 activity is critical to elicit nuclear ATP production following hormone stimulation and a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. The NUDT5 protein is critical for 3D organoid growth of breast cancer cells. Here, we confirm the involvement of NUDT5 in ADP-ribose metabolism and identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can effectively block growth of 3D breast cancer organoids. Citation Format: T Helleday. Targeted DNA repair in cancer and new NUDT5 inhibitors to block hormone signalling to target breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES12-2.