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. Author manuscript; available in PMC: 2021 Dec 8.
Published in final edited form as: Sci Signal. 2021 Jun 8;14(686):eabc7405. doi: 10.1126/scisignal.abc7405

Figure 6. Mechanism of action NAMPT inhibitors plus BH3 mimetics.

Figure 6.

TNBC cells that are sensitive to the combination treatment of a NAMPT inhibitor and a BH3 mimetic are reliant on NAMPT to maintain critical levels of NAD+. In these cells, other NAD+ synthesis pathways, with NAPRT and TDO and IDO as rate-limiting enzymes, cannot compensate for NAMPT inhibition and NAD+ levels drop below a critical threshold. While several metabolic pathways are dysregulated, it is adenine depletion in particular that increases the mitochondrial apoptotic priming. TNBC cells that are insensitive to the combination treatment activate compensatory NAD+ synthesis pathways upon NAMPT inhibition. While NAD+ levels drop, they remain above the critical threshold and no increased mitochondrial apoptotic priming is observed.