PSUN347 A Novel Mechanism-based Inhibitor of Ribonucleotide Reductase is Highly Effective in Preclinical Models of Endocrine Therapy-Resistant Breast Cancer

Abstract Approximately 70% of breast cancers express Estrogen Receptor (ER), and patients with ER+ disease benefit from first-line targeted anti-hormone therapies (e. g. tamoxifen). However, at least 30% develop therapeutic resistance. Second-line therapy includes CDK4/6 inhibitors, yet nearly uniformly resistance to these drugs as well, highlighting the need identify additional targets in resistant tumors. In this regard, tamoxifen-resistant cancer cells tumors display increased expression several key cell cycle chromosomal maintenance-related genes. This elevated genes Chromosomal Instability (CIN70) signature, comprising 70 that promote CIN facilitate tumor progression. RRM2 is one such gene encodes small subunit Ribonucleotide Reductase (RNR). public RNA-seq data, was most differentially expressed CIN70 tumors, associated poor patient outcomes. We hypothesized drives subsequent tamoxifen resistance, targeting or RNR activity will exacerbate intolerable levels, leading drug-resensitization death. confirmed multiple lines compared their parental counterparts. Moreover, we found also exhibit phenotypes indicated by nuclear defects (micro-, multi-, dysmorphic nuclei). As a model intrinsic endocrine therapy, examined triple-negative (TNBC) lack ER have cells. These data affirm utility for treating aggressive disease. While there are five currently approved they cause significant toxicities due chelator mechanism action. To address limitation, developed novel mechanism-based inhibitor catalytic (RRM127) less toxic mouse models. demonstrate RRM127 induces excessive high expression. Most importantly, suppresses growth both line patient-derived TNBC xenografts mice. Together, results indicate its inhibition has strong efficacy preclinical models cancer. Current studies focused on identifying mechanisms which blocks growth. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30