Figure 2.

Inhibition of proteasome inhibitor (PI) and PI3K/AKT/mTOR pathway results in synergistic cellular death. The PI3K/AKT/mTOR pathway is a central signaling hub in eukaryotic cells and it is connected to the ubiquitin–proteasome system (UPS) by balancing amino acid homeostasis (amino acid pool). Intensive feedback loops between mTORC1, mTORC2, and AKT pose a challenge to the successful inhibition of this pathway. Rapalogs target the mTORC1 complex; the mTORC1/mTORC2 dual inhibitor pp242 (torkinib) is more effective in combination with PI. The PI3K inhibitors copanlisib and TGR-1202 demonstrated synergistic cytotoxicity with PI. Several AKT inhibitors (perifosine, TAS-117, nelfinavir, montelukast) were found to synergize with (PI) by affecting endoplasmic reticulum (ER) stress, ERK, or c-Myc.