Binding of antigen/autoantigen to the BCR results in formation of the signalosome that includes SYK, BTK, and PI3K, all of which have been targeted by kinase inhibitors that have shown promise for the treatment of CLL. However, the PI3K complex also regulates signaling from IL-4, CD40L, CXCL12, BAFF, and the Toll-like receptor (TLR). Several signaling pathways are activated downstream of these kinases, which results in the elevation of NFAT, MYC, JUN, nuclear factor-κB (NF-κB), S6, Bim, Noxa, and β-catenin, which are involved in survival, apoptosis, proliferation, and migration. Mammalian target of rapamycin (mTOR) immediately downstream of PI3K/AKT signaling is the catalytic subunit of the mTORC1 and mTORC2 complexes. mTORC2 is capable of inducing a positive feedback loop that leads to the phosphorylation of serine 473 (P S473) and reactivation of AKT downstream signaling.