Role of Diacylglycerol kinase alpha (DGKA) as a therapeutic target in Glioblastoma (GB)

Glioblastoma (GB) is the most common high-grade fatal brain tumor. The standard of care treatment is surgery, followed by radiotherapy and chemotherapy. Despite decades of research, the median life expectancy of patients is still between 12 to 15 months. The activation of multiple receptor tyrosine kinases (RTKs) and/or downstream tumour-intrinsic mutations provide oncogenic stimuli to GB progression and accounts for resistance to current therapies. Identifying a target that is capable of simultaneously disabling of multiple, parallel oncogenic signals can represent an effective therapy. Mounting reports indicate DGKα relevance as a therapeutic target across multiple cancers, given its role in different aspects of tumour biology. DGKα phosphorylates diacylglycerol (DG) resulting in the production of phosphatidic acid (PA). Both DG and PA are membrane bound secondary messengers that regulate signalling molecules involved in cancer. DGKs act simultaneously as both terminators and activators of DG- and PA-mediated signalling. In order to exploit DGKα as a therapeutic target we investigated the role of DGKα in GB biology and signalling. Our results show that DGKα is required for GB stem-like cell long term viability and stemness maintenance and sensitize tumor cells to temozolomide. Inhibition of DGKα strongly impairs NF-κB transcriptional activity and analysis of the TNFR signalling showed that DGKα is necessary for FAK and AKT activation downstream TNFa stimulation. Taken together, the results of this study strongly suggest that DGKα plays a key role in stemness maintenance contributing FAK, Akt and NF-kB activation upon TNF stimulation and for this reason DGKa might represent a targetable oncogene that links inflammation and tumor growth and progression.