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

by Selleckchem | Aug 03 2023

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.

Comments:

The study you described highlights the potential of targeting NAMPT, an enzyme involved in NAD+ metabolism, as a novel strategy for treating metastatic breast cancer. The researchers found that NAMPT was increased in metastatic breast cancer cells treated with fulvestrant (Fulv), an endocrine therapy drug that targets estrogen receptor-α (ERα).

The study aimed to determine whether blocking NAD+ production through inhibition of NAMPT could enhance the effectiveness of standard-of-care therapies for ER+ metastatic breast cancer. The researchers tested the combination of the NAMPT inhibitor KPT-9274 with palbociclib, tamoxifen, or other metabolic inhibitors, but they did not observe a synergistic effect. However, when KPT-9274 was combined with fulvestrant, they found a synergistic reduction in metastatic tumor burden.

Further analysis was conducted using RNA-sequencing and metabolomics analysis. The combination of NAMPT inhibition and fulvestrant was found to reverse the expression of gene sets associated with a more aggressive tumor phenotype and reduce the abundance of metabolites involved in key tumor metabolic pathways.

The study suggests that targeting metabolic adaptations in endocrine-resistant metastatic breast cancer, specifically through the combination of NAMPT inhibition and antiestrogen therapy, could be a promising approach to reduce tumor burden and metastasis. These findings provide insights into the cross-talk between ERα and NAMPT in metastatic breast cancer and offer potential new avenues for the treatment of this challenging condition.