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

Approximately 70% of human breast cancers express estrogen receptor-a (ERa), providing a potential target for endocrine therapy. However, 30%–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 NAMPT, an important enzyme in nicotinamide adenine dinucleotide (NAD+) metabolism, to be increased in metastatic breast cancer (MBC) cells treated with Fulv. We tested whether blockade of NAD+ production via inhibition of nicotinamide phosphoribosyltransferase (NAMPT) synergizes with standard-of-care therapies for ER+ metastatic breast cancer 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 fulvestrant (Fulv) works synergistically to reduce metastatic tumor burden. RNA-sequencing analysis showed that NAMPT inhibition improved antiestrogenic activity of Fulv, 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 metastatic breast cancer 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 ERa–NAMPT cross-talk in metastatic breast cancer and the utility of NAMPT inhibition and antiestrogen combination therapy in reducing tumor burden and metastasis, potentially leading to new avenues of metastatic breast cancer treatment. Overall design: Comparative gene expression profiling analysis of RNA-seq data for liver tumors derived from MCF7 Y537S cells under various treatments (Fulv, Fulv+NAMPi,Fulv+Palb,Palb,Palb+NAMPTi)