Abstract 4854: Targeting ribonucleotide reductase M2 using didox causes inhibition of estrogen receptor-negative, inflammatory breast cancer cell proliferation and tumor emboli formation in culture

Abstract

Abstract Ribonucleotide reductase (RR) catalyzes the conversion of ribonucleotides to deoxyribonucleotides during the rate-limiting step of DNA synthesis. Given its significant role in cell cycle regulation, RR and its catalytic subunits are significant molecular targets for inhibiting tumor cell growth and proliferation. Didox (3,4-dihydroxybenzohydroxamic acid) is a known inhibitor of the catalytic RR subunit of RRM2 and overall DNA synthesis. Previous meta-analyses have revealed that RRM2 is highly expressed in estrogen receptor-negative (ER-) breast cancer tumors. As ER negativity is frequent in inflammatory breast cancer (IBC), a distinct and the most aggressive breast cancer subtype, we proposed to evaluate efficacy of didox in IBC cell models. ER- inflammatory breast cancer (IBC) cell lines SUM149 (ER-, PR-, EGFR-activated), lapatinib-resistant SUM149 (rSUM149), and non-IBC BT474M1 metastatic subline of BT474 (ER+, PR+, HER2+) were compared for the cytotoxic and cytostatic effects of didox using cell viability (trypan blue exclusion) and proliferation (MTT) assays. Protein profiling was performed to evaluate changes in molecular expression of key proteins involved in cellular signaling pathways for apoptosis and proliferation. Only ER- cell lines exhibited decreased dose-dependent decrease in viability following didox treatment. In addition, didox inhibited tumor emboli formation in a novel ex vivo tumor emboli in culture assay that mimics the clinicopathologic hallmark of IBC disease in patients. Moreover, didox decreased proliferation in lapatinib-resistant rSUM149, suggesting that the drug may help circumvent lapatinib resistance. Studies are ongoing to evaluate the mechanism of didox in overcoming lapatinib resistance and evaluation in an in vivo IBC invasion model. IBC is rare but accounts for 10% of breast cancer deaths, and despite multimodal therapy the 5-yr survival is only 25-55%. Further, there is a need to identify new therapies that can inhibit IBC tumor emboli formation and migration. Didox has demonstrated minimal toxicity in human phase I/II cancer clinical trials and therefore is an attractive strategy for inflammatory breast cancer therapy. Support in part from the Development funds (GRD) of the Duke Cancer Institute as part of the P30 Cancer Center Support Grant NIH CA014236 and Department of Defense Breakthrough Level 2 W81XWH-17-1-0297 (GRD). Citation Format: Pranalee Patel, Ben Mirman, Renzhi Zhan, Gayathri R. Devi. Targeting ribonucleotide reductase M2 using didox causes inhibition of estrogen receptor-negative, inflammatory breast cancer cell proliferation and tumor emboli formation in culture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4854.