NAD+ metabolism restriction boosts high-dose melphalan efficacy in patients with multiple myeloma

Area of Science:

• Biochemistry
• Oncology
• Metabolic pathways

Background:

• Elevated nicotinamide phosphoribosyltransferase (NAMPT) is common in cancers, including multiple myeloma (MM).
• Previous NAMPT inhibition strategies failed in clinical trials due to alternative NAD+ production routes.
• NAD+ metabolism is dysregulated in MM cells, necessitating a deeper understanding of its biosynthesis pathways.

Purpose of the Study:

• To define the specific NAD+ landscape in multiple myeloma (MM) cells.
• To identify alternative NAD+ biosynthesis pathways that confer resistance to NAMPT inhibitors.
• To evaluate the therapeutic potential of targeting both NAMPT and nicotinate phosphoribosyltransferase (NAPRT) in MM.

Main Methods:

• Mathematical modeling integrated with transcriptome data to analyze NAD+ metabolism.
• Transcriptomic, metabolic, and bioenergetic profiling of NAPRT-knockout (KO) MM cells.
• Assessing the effects of combined NAMPT and NAPRT inhibition on MM cell sensitivity to chemotherapy.

Main Results:

• The Preiss-Handler pathway, utilizing nicotinic acid via NAPRT, supports NAD+ synthesis in MM cells.
• NAPRT confers resistance to NAD+-depleting agents, and its absence weakens MM cell antioxidant defenses and increases oxidative stress.
• Combined NAMPT and NAPRT inhibition sensitizes MM cells to melphalan, with NAPRT re-addition fully rescuing these effects.

Conclusions:

• Comprehensive NAD+ biosynthesis inhibition by targeting both NAMPT and NAPRT is a viable therapeutic strategy for MM.
• This dual-targeting approach could overcome resistance mechanisms observed with NAMPT inhibition alone.
• The findings support testing dual NAMPT and NAPRT inhibition in clinical trials for transplant-eligible MM patients, particularly those with aggressive disease.