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. Author manuscript; available in PMC: 2022 Apr 1.
Published in final edited form as: Mol Cancer Ther. 2021 Jul 12;20(10):1836–1845. doi: 10.1158/1535-7163.MCT-20-1105

Figure 6: Mechanism of action of KPT-9274 in PNET cells.

Figure 6:

mTORC2 regulates resistance to everolimus in NET cells. Everolimus inhibits mTORC1 and its downstream effectors 4EBP-1 and P70S6K by preventing mTORC1 to interact with its intracellular receptor FKBP12 which induces mTORC2 to phosphorylate AKT thus promoting PI3K/AKT/mTOR signaling. KPT-9274 inhibits PAK4 which downregulates RICTOR then alters the activation of mTORC2. Inhibition of PAK4 also downregulates β-CATENIN. Inhibition of NAMPT reduces the cellular level of NAD and ATP. All the latter events promote PNETs shrinkage.