Pancreatic neuroendocrine tumors: Therapeutic challenges and research limitations

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.