NAD⁺ Metabolism Generates a Metabolic Vulnerability in Endocrine-Resistant Metastatic Breast Tumors in Females

Approximately 70% of human breast cancers express estrogen receptor-α (ERα), providing a potential target for endocrine therapy. However, 30% to 40% of patients with ER⁺ breast cancer still experience recurrence and metastasis, with a 5-year relative overall survival rate of 24%. In this study, we identified nicotinamide phosphoribosyltransferase (NAMPT), an important enzyme in nicotinamide adenine dinucleotide (NAD⁺) metabolism, to be increased in metastatic breast cancer (MBC) cells treated with fulvestrant (Fulv). We tested whether the blockade of NAD⁺ production via inhibition of NAMPT synergizes with standard-of-care therapies for ER⁺ MBC in vitro and in vivo. A synergistic effect was not observed when KPT-9274 was combined with palbociclib or tamoxifen or when Fulv was combined with other metabolic inhibitors. We show that NAMPT inhibitor KPT-9274 and Fulv works synergistically to reduce metastatic tumor burden. RNA-sequencing analysis showed that NAMPT inhibitor in combination with Fulv reversed the expression of gene sets associated with more aggressive tumor phenotype, and metabolomics analysis showed that NAMPT inhibition reduced the abundance of metabolites associated with several key tumor metabolic pathways. Targeting metabolic adaptations in endocrine-resistant MBC is a novel strategy, and alternative approaches aimed at improving the therapeutic response of metastatic ER⁺ tumors are needed. Our findings uncover the role of ERα–NAMPT crosstalk in MBC and the utility of NAMPT inhibition and antiestrogen combination therapy in reducing tumor burden and metastasis, potentially leading to new avenues of MBC treatment.