Model for CC-115 mechanism of action: schematic representing proposed mechanism by which CC-115 induces cytotoxicity in CLL tumor cells. mTOR is a highly conserved serine/threonine kinase downstream of PI3K/AKT that forms multimolecular complexes with key functions in cell growth, proliferation, and survival. The mTOR kinase can complex with Raptor (regulatory-associated protein of mTOR) to form mTORC1, or with Rictor (rapamycin-insensitive companion of mTOR) to form mTORC2. Once phosphorylated by the upstream PI3K/AKT kinases, mTORC1 activates its downstream effectors (eg, 4EBP1, p70S6K1) to stimulate protein synthesis and cell cycle entry. mTORC2 acts upstream of mTORC1 by inducing phosphorylation of AKT on serine 473, which creates a positive feedback loop that contributes to cell survival. The survival signal mediated by mTORC2 is thought to account for the resistance to mTORC1 inhibitors (ie, rapamycin and its analogs). In contrast, CC-115 inhibits both mTORC1 and mTORC2, and leads to growth arrest and apoptosis. Furthermore, CC-115 inhibits NHEJ DNA repair by preventing the recruitment of DNA-PK to DSB. This causes persistence of DNA damage and cell death. Professional illustration by Somersault18:24.