Figure 2.

Emerging combination therapy: Combined blockage of glutaminolysis with inhibition of other pathways.

CB-839 or BPTES, small molecule inhibitors of GLS, combined with other drugs, is an emerging cancer treatment strategy. (1) CB-839 combinations: CB-839 combined with cabozantinib, a small molecule inhibitor of growth factor signaling, or with everolimus, an mTOR inhibitor, are currently undergoing clinical trials. In addition, CB-839 synergizes with nivolumab, a human IgG4 monoclonal antibody blocking PD-1, and this combination is also undergoing a Phase II clinical trial. Poly (ADP-ribose) polymerase (PARP) is important for cancer cells to reduce ROS stress and sustain genome integrity. GLS inhibition by, e.g. CB-839 treatment, suppresses the generation of nucleotides and causes replication stress, which may activate PARP-dependent DNA repairs. Treating cancer cells with a combination of CB-839 and PARP inhibitor, such as olaparib, has been shown to achieve synergistic antitumor activity. NAAG has been identified as a glutamine reservoir in cancer cells and is hydrolyzed to generate glutamate and NAA by carboxypeptidase II (GCPII), which can be inhibited by 2-PMPA. Combining 2-PMPA with CB-839 showed a more significant decrease in tumor size compared to treating the tumor with either of these drugs alone. (2) BPTES combination: BPTES combined with metformin, a glucose metabolism inhibitor, results in greater inhibition of tumor growth. The glutaminase II pathway provides cancer cells with a mechanism for bypassing GLS inhibition. Inhibition of both GLS1/2 and the glutaminase II pathway is a novel strategy for treating glutamine-addicted cancers. The effect of each drug or shRNA (highlighted in yellow) is shown in red, metabolites are shown in black, and enzymes are shown in blue boxes.