Molecular Pathways: Targeting Diacylglycerol Kinase Alpha in Cancer
1Department of Neurology, University of Virginia, Charlottesville, Virginia. bwp5g@virginia.edu.
Abstract:
Lipid kinases have largely been neglected as targets in cancer, and an increasing number of reports suggest diacylglycerol kinase alpha (DGKα) may be one with promising therapeutic potential. DGKα 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 DGKα, including the c-Met and VEGF receptors. Others partially mediate the effects of DGKα inhibition in cancer, such as mTOR and HIF-1α. DGKα 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 DGKα were established decades ago, they have seen minimal in vivo usage, and it is unlikely that either of these older DGKα inhibitors will have utility for cancer. An abandoned compound that also inhibits serotonin receptors may have more translational potential as a DGKα inhibitor, but more potent and specific DGKα inhibitors are sorely needed. Other DGK family members may also provide therapeutic targets in cancer, but require further investigation.
Insights
Diacylglycerol kinase alpha (DGKα) is a promising cancer target. Inhibiting DGKα impairs cancer cell viability, angiogenesis, and boosts immunotherapy, though better inhibitors are needed.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Diacylglycerol kinase alpha (DGKα) regulates lipid second messengers diacylglycerol (DAG) and phosphatidic acid (PA).
- DGKα is implicated in oncogenic pathways involving c-Met and VEGF receptors, and influences mTOR and HIF-1α.
- DGKα is an emerging, yet under-explored, target in cancer therapy.
Purpose of the Study:
- To review the therapeutic potential of diacylglycerol kinase alpha (DGKα) as a cancer target.
- To discuss the role of DGKα in cancer cell viability, angiogenesis, and immunotherapy.
- To evaluate existing DGKα inhibitors and highlight the need for novel therapeutic agents.
Main Methods:
- Literature review of DGKα's role in cancer.
- Analysis of oncogenic pathways influenced by DGKα.
- Assessment of current and potential DGKα inhibitors.
Main Results:
- DGKα inhibition impairs cancer cell viability and angiogenesis.
- DGKα inhibition may enhance T-cell activation and cancer immunotherapy.
- Existing DGKα inhibitors have limitations; novel, potent, and specific inhibitors are required.
Conclusions:
- DGKα represents a promising therapeutic target for cancer treatment.
- Further investigation into DGKα and related family members is warranted for developing new cancer therapies.
- Development of improved DGKα inhibitors is crucial for clinical translation.
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