Using TBK1 Inhibitors to Stop Cancer in Its Tracks

TBK1 Inhibitors, Autoimmune Disorders, and Cancer – Inflammation is a crucial step within the immune response, helping our bodies eliminate disease. However, it can also be a burden where misregulation creates a variety of maladies including cancer. As inflammation persists, becoming chronic, the beneficial elements can be lost and disease occurs. It’s not just autoimmune disorders that lead to chronic inflammation. Researchers believe there are a range of contributors these days including chemicals, pollutants, alcohol, obesity, and chronic stress, which are all common influences in most of our lives.

Persistent inflammation drives tumor initiation and continues to play a role in tumor promotion, malignant conversion, and metastasis. Furthermore, immune mediators such as cytokines, chemokines, growth factors, and free radicals can stimulate tumor development and its microenvironment.

The Role of TBK1 in Inflammation and Cancer

Foreign DNA such as virus or bacteria alerts the immune system, but so does damaged DNA. In these instances, the “bad” DNA is in the cytosol waiting to be destroyed vs. the mitochondria or nucleus which is typically where DNA is located. This cytosolic DNA is what sets the STING (stimulator of interferon genes) signaling pathway in motion. It gets recognized by cGAS, which allows cGAMP (a cyclic di-nucleotide formed in response to double-stranded DNA (dsDNA) in the cytosol) to bind to STING.²

TBK1 is a critical player in initiating inflammation as it has the ability to regulate proteins such as IFN-β, an inflammatory mediator. When TBK1 phosphorylates STING, it becomes more accessible for the binding of IRF3. TBK1 then phosphorylates IRF3, which translocates to the nucleus to drive transcription of IFN-β.¹  IFN-β expression has been found in tumor-derived DNA in the cytosol of dendritic cells.¹

TBK1 Inhibitors Show Promise

Hence, targeting TBK1 to decrease inflammation when it becomes chronic is a logical choice. One in which scientists’ have already started capitalizing on as is the case of TBK1 inhibitor, BX795.³ Although progress has been made, there’s still potential in targeting TBK1 directly in order to curb inflammation and keep cancer at bay. More researchers are getting on board as chronic inflammation and cancer are significant health issues leading to fatality. According to CDC, cancer is the second leading cause of death in the US.

Since TBK1 is a protein kinase, the Transcreener ADP² Assay is ideal for measuring the activity of the enzyme, which is necessary when screening possible inhibitors for therapeutic potential. This assay can be used for high throughput screening (HTS) and hit-to-lead programs. Additionally, the technique is easy to use, safe, sensitive, and robust.

References

1. Corrales L, McWhirter SM, Dubensky TW, Gajewski TF. The host STING pathway at the interface of cancer and immunity. J Clin Invest. 2016;126(7):2404-2411. doi:10.1172/JCI86892
2. Li T, Chen ZJ. The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer. J Exp Med. 2018;215(5):1287-1299. doi:10.1084/jem.20180139
3. Yu T, Yi Y-S, Yang Y, Oh J, Jeong D, Cho JY. The Pivotal Role of TBK1 in Inflammatory Responses Mediated by Macrophages. Mediators Inflamm. 2012;2012:1-8. doi:10.1155/2012/979105