Figure 5.

Emerging combinations with Rapalogs. Rapalogs only partially inhibit mTORC1 signaling. Already available drugs (approved or under clinical evaluation) can be combined with rapalogs in order to induce tumor cell killing. By inhibited S6K phosphorylation, rapalogs prevent the negative feedback loop on PI3K/Akt, resulting in PI3K/Akt activation. mTORC1 can be targeted with upstream kinases involved in BCR signaling (with anti-CD20 antibody or the PKC inhibitor AEB071, or the BTK inhibitor Ibrutinib) or in Akt signaling (with HDAC inhibitors, panobinostat or vorostinat). Hydrolysis of amino acids that are required for mTORC1 activation, such as arginine (with L-arginase), or glutamine (L-asparaginase), can further abolish mTORC1 signaling and induce cell death when combined with rapalogs. mTORC1-dependent regulation of metabolism is essential to induce an anabolic program promoting cell growth. Combined Rapalogs with inhibitor of glycolysis (MCT1 inhibitor, AZD3965), or mitochondrial complex I activity (Metformin) or gutaminolysis (GLS inhibitor, CB-839) or nucleotide synthesis (Methotrexate or Gemcitabine or Fludarabine or cytarabin), might improve patient's response. Importantly, the choice of the anti-metabolic strategy depends on the metabolic status of the tumor cells. PKC, Protein Kinase C; BTK, Bruton's Tyrosine Kinase; HDAC, histone deacetylase; MCT, Monocarboxylate Transporter.