Unraveling the role of nicotinamide phosphoribosyltransferase (NAMPT) in triple-negative breast cancer: insights into metastatic dynamics

NAM PT is a key intracellular enzyme that sustains NAD+ levels. Indeed, intrecellular NAM PT (iNAMPT) overexpression in various malignancies supports tumor metabolism. iNAMPT inhibitors like FK866 show favorable results by depleting NAD+ in cancer cells, but systemic NAD+ depletion causes several toxicities. PROTACs, which degrade NAMPT via the proteasome, offer a promising alternative with reduced side effects. In our work we screened a PROTAC library on TNBC cells, identifying the compound 1142 as the most effective NAMPT degrader since it showed enhanced degradation efficiency and cytotoxicity, making it a promising lead for targeted cancer therapy. However, NAMPT's widespread expression necessitates tumor-specific functionalization to minimize adverse effects. Degraders may offer superior efficacy by eliminating both enzymatic and non-enzymatic functions of NAMPT, reducing its secretion, and interfering with tumor metabolism. Indeed, beyond NAD+ biosynthesis, extracellular NAMPT (eNAMPT) acts as a pro-inflammatory cytokine, influencing the tumor microenvironment. High eNAMPT levels in breast cancer correlate with disease progression. It promotes immune evasion via the PD-L1/PD-1 axis, and its neutralization restores immune activity, reducing tumor size and metastases more effectively than anti-PD-l/PD-Ll treatments. We further demonstrate that eNAMPT drives tumor angiogenesis by recruiting pericytes, activating the NF-KB pathway, and upregulating chemokines (CXCL8, CXCL1, CCL2). The enrichment of eNAMPT in tumors shows increased pericyte-covered vessels, circulating tumor cells (CTCs) number, and metastases. Additionally, we demonstrated that eNAMPT reprograms tumor cells during metastasis, sustaining a hybrid EMT state that enhances CTC clustering and metastatic potential. In conclusion, NAMPT neutralization holds great promise for TNBC treatment by targeting multiple cancer.