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Approximately 70% of human breast cancers express estrogen receptor alpha (ERα), providing a potential for targeted endocrine therapy for patients. Unfortunately, 30-40% of ER+ patients still experience recurrence and metastasis, with a 5-year relative overall survival rate of just 24% for patients with metastatic disease. Previously, we described an increased reliance on NAD+ metabolism in metastatic breast cancer (MBC) cells, which are driven by clonal selection from monotherapy resistance and the metastatic organ microenvironment. In the current study, we investigated if inhibition of NAMPT to block NAD+ production would synergize with standard of care therapies for ER+ MBC. Combination therapy of the NAMPT Inhibitor, KPT9274 and the ERα agonist Fulvestrant (Fulv) synergistically reduced tumor burden in liver metastasis in vitro (combination index < 1 in cell viability assays) and in vivo in mouse xenograft models. A synergistic effect was not observed when KPT-9274 was combined with Palbociclib or Tamoxifen, nor Fulv with other metabolic inhibitors. RNA-Seq analysis showed that NAMPT inhibition restored antiestrogenic activity of Fulv. Metabolomics analysis showed that NAMPT inhibition reduced abundance of metabolites associated with glucose and lipid metabolism. Mechanistically, chromatin immunoprecipitation showed that NAMPT is recruited to ERα binding sites in MBC xenografts and PDX tumors. Targeting metabolic adaptations in endocrine-resistant metastatic breast tumors is a novel approach that could lead to new combined therapies that reduce mortality. Citation Format: Ayca N. Mogol, Christine Chien, Qianying Zuo, Akshara S. Raghavendra, Debu Tripathy, Yosef Landesman, Zeynep Madak Erdogan. ERα and NAMPT crosstalk at enhancers drives Fulvestrant resistance in metastatic breast tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2698. |
