Molecular Pathways: Targeting Diacylglycerol Kinase Alpha in Cancer

Lipid kinases have largely been neglected as targets in cancer, and an increasing number of reports suggest diacylglycerol kinase alpha (DGK alpha) may be one with promising therapeutic potential. DGK alpha is one of 10 DGK family members that convert diacylglycerol (DAG) to phosphatidic acid (PA), and both DAG and PA are critical lipid second messengers in the plasma membrane. A host of important oncogenic proteins and pathways affect cancer cells in part through DGK alpha, including the c-Met and VEGF receptors. Others partially mediate the effects of DGK alpha inhibition in cancer, such as mTOR and HIF-1 alpha. DGK alpha inhibition can directly impair cancer cell viability, inhibits angiogenesis, and notably may also boost T-cell activation and enhance cancer immunotherapies. Although two structurally similar inhibitors of DGK alpha were established decades ago, they have seen minimal in vivo usage, and it is unlikely that either of these older DGK alpha inhibitors will have utility for cancer. An abandoned compound that also inhibits serotonin receptors may have more translational potential as a DGK alpha inhibitor, but more potent and specific DGK alpha inhibitors are sorely needed. Other DGK family members may also provide therapeutic targets in cancer, but require further investigation. (C) 2015 AACR.