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

Abstract

Approximately 70% of human breast cancers express estrogen receptor-α (ERα), providing a potential target for endocrine therapy. However, 30%–40% of patients with ER+ breast cancer still experiences 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 the 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 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 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 ERα–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.

Identification of metabolic pathways contributing to ER+ breast cancer disparities using a machine-learning pipeline

“…Additionally, changes in metabolite levels affect gene and protein expression by altering substrate availability of epigenetic modifiers that mark to the DNA, RNA, and histones, ultimately dictating cancer progression and outcome 46 – 48 . Previous studies 19 – 21 , 49 – 51 and studies from our lab 52 – 55 showed how systemic or cellular metabolic changes impact epigenetic landscape, which is important for ERα activity and response to clinical drugs. Amino acids provide metabolic intermediates for epigenetic regulation.…”

Community cohesion looseness in gene networks reveals individualized drug targets and resistance

“…These results indicate that the dysfunction of these communities neutralize the therapeutic effect of tamoxifen and the genes present in these community could be potential therapeutic targets to reduce resistances based on the individualized mechanisms of endocrine therapy resistance. For example, among the anti-cancer drug targets in the BrC11 ( Supplementary Table S6 ), it has been known that high expression of NAMPT (nicotinamide phosphoribosyl transferase) confers the tamoxifen resistance [ 48 ] and recently it is discovered that combination therapy of NAMPT inhibition and antiestrogen is effective to reduce breast cancer metastasis [ 49 ]. Similarly, there are several pieces of evidence that targeting both ESR1 and RXRA (retinoid X receptor alpha) present in BrC8 ( Supplementary Table S6 ) decreases the tamoxifen resistance [ 50 ].…”

The Role of Amino Acids in the Diagnosis, Risk Assessment, and Treatment of Breast Cancer: A Review

“…Met is a methyl group donor for methylation and is a major contributor to epigenetic regulation [ 78 , 79 ]. Systemic or cellular metabolic changes affect the epigenetic landscape, which is important for ERα activity and the response to clinical drugs [ 80 , 81 ]. In AA women, poverty rates are correlated with the hypermethylation of cancer-associated pathways, including the glucocorticoid receptor, p53, estrogen-dependent breast cancer signaling, and cell proliferation [ 82 ].…”