Review
Copyright ©The Author(s) 2020.
World J Gastroenterol. Jul 28, 2020; 26(28): 4036-4054
Published online Jul 28, 2020. doi: 10.3748/wjg.v26.i28.4036
Figure 1
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Figure 1 Graphical abstract. PFS: Progression free survival; PNET: Pancreatic neuroendocrine tumor.
Figure 2
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Figure 2 Nicotinamide phosphoribosyltransferas’s biological functions. A: Structure of nicotinamide phosphoribosyltransferas (NAMPT). Structure obtained from RSCB Protein Data Bank, Deposited: 2008-06-15 Released: 2009-08-18. Deposition Author(s): Ho, M., Burgos, E.S., Almo, S.C., Schramm, V.L.; B: NAMPT and immune signaling; C: NAMPT signaling in NAD biosynthesis. NAD: Nicotinamide adenine dinucleotide; NAMPT: Nicotinamide phosphoribosyltransferas; eNAMPT: Extracellular Nicotinamide phosphoribosyltransferase; iNAMPT: Intracellular nicotinamide phosphoribosyltransferase; NMNAT: Nicotinamide mononucleotide adenylyltransferase; TNFa: Tumor necrosis factor alpha; IL: Interleukin; MCP-1: Monocyte chemoattractant protein-1; PARP: Poly(ADP-ribose) polymerase.
Figure 3
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Figure 3 Mechanism of action of available PAK4-NAMPT dual inhibitor. Dual inhibition of PAK4 and NAMPT using KPT-9274 single agent or in combination with everolimus results in lower case tumor shrinkage. KPT-9274 inhibits NAMPT causing downregulation of NAD and ATP and alteration of cell metabolism. Additionally, KPT-9274 Inhibits PAK4 resulting in downregulation of β-catenin and RICTOR. Downregulation of RICTOR causes the inhibition of mTORC2 implicated in everolimus resistance. R: Resistance; PAK4: p21-activated kinase 4; NAMPT: Nicotinamide Phosphoribosyltransferase; KPT-9274: Available PAK4-NAMPT dual inhibitor; NAD: Nicotine adenine dinucleotide; ATP: Adenosine-triphosphate; RICTOR: Rapamycin-insensitive companion of Tor; mTORC2: Mammalian target of rapamycincomplex 2.