Nicotinamide N-Methyl Transferase (NNMT) Sustains Innate Sensitivity to NAMPT Inhibition in YAP-dependent...

Area of Science:

• Oncology
• Molecular Biology
• Metabolic Pathways

Background:

• Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors are promising cancer therapeutics, but resistance limits their use.
• Innate resistance mechanisms to NAMPT inhibitors are poorly understood, especially in advanced prostate cancer subtypes.
• Stem cell-like castration-resistant prostate cancer (CRPC-SCL) exhibits unique signaling dependencies and mesenchymal traits.

Purpose of the Study:

• To investigate the mechanisms of innate resistance to NAMPT inhibitors in prostate cancer.
• To identify biomarkers predicting response to NAMPT-targeted therapies.
• To explore therapeutic strategies for stem-like, therapy-resistant prostate cancers.

Main Methods:

• Utilized genetic and pharmacological models in prostate cancer cell lines (PC3, DVL3).
• Employed gene silencing (YAP, NNMT) and FK866 treatment.
• Conducted metabolomic profiling and analyzed clinical CRPC-SCL datasets.
• Assessed *in vivo* tumor aggressiveness in murine models.

Main Results:

• The YAP/nicotinamide N-methyltransferase (NNMT) axis was identified as a key regulator of innate FK866 sensitivity.
• Silencing YAP or NNMT protected cells from FK866-induced apoptosis, ER stress, and NAD(H) depletion.
• NNMT activity was shown to deplete nicotinamide, sensitizing cells to FK866.
• NNMT upregulation correlated with mesenchymal and therapy-resistant phenotypes in clinical CRPC-SCL data.
• Mesenchymal prostate cancer cells overexpressing NNMT showed increased sensitivity to FK866.

Conclusions:

• The YAP/NNMT axis determines innate sensitivity to NAMPT inhibition in prostate cancer.
• NNMT serves as a predictive biomarker for NAD+-targeting therapies.
• Targeting the YAP/NNMT/NAMPT axis offers a potential strategy for treating aggressive, therapy-resistant prostate cancers.