New strategies to maximize therapeutic opportunities for NAMPT inhibitors in oncology

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is crucial for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis in mammalian cells. NAMPT inhibitors represent multifunctional anticancer agents that act on NAD(+) metabolism to shut down glycolysis, nucleotide biosynthesis, and ATP generation and act indirectly as PARP and sirtuin inhibitors. The selectivity of NAMPT inhibitors preys on the increased metabolic requirements to replenish NAD(+) in cancer cells. Although initial clinical studies with NAMPT inhibitors did not achieve single-agent therapeutic levels before dose-limiting toxicities were reached, a new understanding of alternative rescue pathways and a biomarker that can be used to select patients provides new opportunities to widen the therapeutic window and achieve efficacious doses in the clinic. Recent work has also illustrated the potential for drug combination strategies to further enhance the therapeutic opportunities. This review summarizes recent discoveries in NAD(+)/NAMPT inhibitor biology in the context of exploiting this new knowledge to optimize the clinical outcomes for this promising new class of agents.

Keywords: DNA damage; NAMPT; NAPRT1; PARP; niacin.

Figure 1.

Pathways involved in NAD⁺ biosynthesis and catabolism. Metabolites: NA, nicotinic acid or niacin; TRP, tryptophan; QA, quinolinic acid; NAMN, NA mononucleotide; NAAD, nicotinic acid adenine dinucleotide; NAD⁺, nicotinamide adenine dinucleotide (oxidized); NM, nicotinamide; NMN, NM mononucleotide; NR, nicotinamide riboside. Metabolic enzymes are: NAPRT1, nicotinic acid phosphoribosyltransferase; NMNAT1,2,3, nicotinamide nucleotide adenylyltransferases; NADS, NAD⁺ synthetase; PARPs, poly ADP-ribose polymerases; SIRTs, sirtuins; CD38, cluster of differentiation 38 or cyclic ADP-ribose hydrolase; NAMPT, nicotinamide phosphoribosyl transferase; NRK1,2, nicotinamide riboside kinases; Cx43, connexin43; CD73, cluster of differentiation 73 or ecto-5′-nucleotidase.

Figure 2.

Mechanism of synergy between DNA damaging agents and NAMPT inhibitors. NAMPTi synergize with several DNA damaging agents, all of which have been shown to induce base excision repair (BER) or single-stranded DNA damage resulting in PARP activation. The increased consumption of NAD⁺ caused by PARP activation combined with inhibition of NAD⁺ regeneration leads to catastrophic NAD⁺ depletion and cell death. In cells that do not reach the threshold level/duration of NAD⁺ depletion, accumulation of unrepaired DNA may later lead to cell cycle arrest and tumor cell death. BER, base excision repair; NAD⁺, nicotinamide adenine dinucleotide (oxidized); NAMPT, nicotinamide phosphoribosyl transferase; NAMPTi, NAMPT inhibitor; PARP, poly ADP-ribose polymerase.