OR30-2 Targeting Succinate Metabolism in Endocrine Therapy Resistant, ER Positive, Breast Cancer Cells

Abstract Estrogen receptor positive (ER+) breast cancer is the most common subtype among all cancers and responsible for related deaths. Endocrine therapies, such as selective estrogen modulators (SERM) aromatase inhibitors (AI), often given in combination with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, are initially effective but majority of advanced ER+ eventually become refractory to endocrine therapies. Therefore, understanding underlying molecular mechanisms that enable or promote resistance therapies may lead novel therapeutic targets.Cancer cells have a high energy demand result consume greater quantities glucose meet their anabolic demands support cell growth proliferation. In this study, we used models therapy sensitive resistant investigated metabolic flux by growing presence stable isotope, UC13-Glucose. We measured C13-labelled metabolites glycolysis TCA cycle. Glucose consumption was higher MCF7/LCC9 (LCC9) compared parental MCF7 (MCF7) independent, MCF7/LCC1 (LCC1) cells. Notably, LCC9 m+4 m+6 isotopomer C-13 labelled citrate absent. Further, cells, fumarate very low while succinate: ratio markedly higher. These results suggest cycle impaired conversion succinate dysregulated. Succinate dehydrogenase (SDH) enzyme catalytic fumarate. SDH multimeric protein comprised four different subunits assembly factor 2 (SDHAF2), which tumor suppressor gene. Our study further showed SDHAF2 under expressed LCC1 likely contributing lower activity. Intriguingly, when activity inhibited using dimethylmalonate, were re-sensitized both Fulvestrant 4-hydroxytamoxifen. Data analysis clinical samples shows poor relapse free survival patients correlated expression levels SDHAF2. Overall, suggests targeting metabolism help restore sensitivity tamoxifen Presentation: Tuesday, June 14, 2022 10:00 a.m. - 10:15