The IKB kinase (IKK) family includes TANK-binding kinase 1 (TBK1) as a member. Recent scientific investigations demonstrate TBK1's essential function in cancer development and its resistance to treatment. TBK1 functions as a vital component in inflammatory processes along with metabolic control and cancer cell longevity while also contributing to anti-tumor immune defense. The use of small molecule inhibitors and combination therapies against TBK1 represents a key advancement in cancer treatment because TBK1 plays a crucial role in KRAS mutant cancers and facilitates both immune escape and drug resistance.
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The Mechanism of Action of TBK1 in Cancer Cells
TBK1 functions in cancer cells by stimulating tumor development and preventing programmed cell death while managing inflammatory responses and immune evasion mechanisms.TBK1 controls multiple signaling pathways within cancer cells where it functions to advance tumor growth while preventing cell apoptosis and managing inflammation and immune escape capabilities.
Promoting Cancer Cell Survival and Proliferation
The activation of NF-κB through TBK1-mediated phosphorylation of IKKε enables control over anti-apoptotic genes such as BCL-XL and XIAP. Through the PI3K-AKT-mTOR pathway TBK1 activates AKT which leads to increased cancer cell growth and their metabolic adaptation.
Inducing Anti-apoptosis and Drug Resistance
TBK1 strengthens cancer cells against chemotherapy and targeted treatments by blocking apoptotic proteins including BIM and BAD. The C-RAF-MEK-ERK pathway controlled by TBK1 preserves cell survival in KRAS mutant non-small cell lung cancer (NSCLC) while causing resistance to MEK inhibitors.
TBK1 as a Target for Cancer Therapy
TBK1 has emerged as a potential anticancer target because it functions within several cancer-associated signaling pathways. BX795 and MRT67307 TBK1 inhibitors demonstrate dual functionality by obstructing TBK1 action and enhancing cancer cell sensitivity to chemotherapy and immunotherapy. Using TBK1 inhibitors alongside PD-1/PD-L1 antibodies leads to enhanced T cell activity and better results in immunotherapy treatments.TBK1 inhibitors + MEK/AKT inhibitors: KRAS mutant tumor drug resistance can be overcome through combination treatments involving TBK1 inhibitors. TBK1 inhibitors + autophagy inhibitors (such as HCQ): Using TBK1 inhibitors alongside autophagy inhibitors blocks cancer cell metabolic changes to boost treatment results.
Upstream Kinases of TBK1 and Direct Activation Mechanisms
The kinase TBK1 functions within the IκB kinase family and its activity depends primarily on upstream kinases or adaptor proteins which trigger its direct phosphorylation-dependent activation. This section lists known upstream kinases that activate TBK1 directly along with their activation mechanisms.
Fig. 1 Role of TBK1 in cancer pathogenesis and anticancer immunity (Runde, A., et al. 2022).
IKK-related Kinases
TBK1 and IKKε share similar structural features and function together to control various signaling pathways. TBK1 activity enhancement occurs through autophosphorylation and cross-phosphorylation between TBK1 which is promoted by IKKε. The activation mode plays a crucial role for antiviral immune responses as well as NF-κB and interferon (IFN)-related signaling pathways.
TLR and PRR-related Kinases
The proteins Receptor interacting protein kinases 1 and 3 (RIPK1 and RIPK3) regulate both apoptosis and necroptosis by phosphorylating TBK1 directly. The RIP homotypic interaction motif (RHIM) domain empowers RIPK1 to induce TBK1 activity during TNF-α-induced cell death which subsequently modifies the NF-κB signaling pathway.
TAK1 (MAP3K7)
TAK1 (TGF-β activated kinase 1) belongs to the MAP3K family and functions as a direct kinase that phosphorylates TBK1 to activate it. TAK1 functions to enable TBK1 to phosphorylate IRF3 which triggers IFN production in antiviral defenses that rely on Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs).
STING-associated Kinases
The proteins TBKBP1 and NAP1 function as adaptor molecules for TBK1 and boost its activity levels. During STING-dependent type I interferon signaling TBKBP1 and NAP1 function as activators of TBK1 which leads to increased phosphorylation of IRF3.
TBK1 Coordinates Inflammation and Metabolism by Regulating Downstream Signaling Pathways
Inflammatory Signaling Regulation
TBK1 enhances IFN-I production through phosphorylation of IRF3 and IRF7 resulting in improved antiviral and anti-infection defenses. TBK1 causes NF-κB pathway activation which controls the release of inflammatory factors such as IL-6, TNF-α, and CXCL10.
Metabolic Regulation
Activation of the AMPK pathway by TBK1 enables fatty acid oxidation and mitochondrial stability maintenance in addition to cellular energy metabolism management. TBK1 activates mTORC1 to induce autophagy which enables tumor cells to endure nutrient scarcity and hypoxic conditions.
TBK1 Regulates Proliferation and Survival of Malignant Cells in Various Cancers
TBK1 serves as a survival promoter and drug resistance factor across multiple tumor types by employing these specific mechanisms:
Promoting Cancer Cell Proliferation
The TBK1 protein enhances tumor expansion through the KRAS-RAF-MEK-ERK pathway specifically in lung cancers with KRAS mutations and pancreatic cancer. The activation of the AKT/mTOR pathway by TBK1 leads to increased metabolism in cancer cells and promotes their rapid growth.
Inhibit Cell Apoptosis
TBK1 blocks programmed cell death by activating anti-apoptotic genes such as BCL-XL and XIAP through NF-κB signaling. TBK1 protein generates chemotherapy resistance by blocking BAD/BIM which leads to resistance in tumor cells against MEK and PI3K inhibitors.
Driving Tumor Drug Resistance
TBK1 triggers resistance to MEK inhibitors such as Trametinib in KRAS mutant lung cancer cells by stimulating C-RAF-dependent signaling pathways. TBK1 protein activates autophagy which functions as a protective survival mechanism allowing cancer cells to resist metabolic stress.
TBK1 Drives Cell Survival Pathways While Inhibiting Apoptosis and Immune Detection and Regulating Metabolic Pathways
TBK1 demonstrates multifunctional kinase characteristics where it undergoes direct phosphorylation and activation through multiple upstream kinases that predominantly regulate inflammation, immune defense mechanisms and metabolic pathways. The kinases IKKε, RIPK1/3, TAK1, AMPK and TBKBP1/NAP1 directly activate TBK1. IKKε and RIPK1/3 among others function as key activators that directly trigger TBK1. TBK1 and its upstream kinases present as potential targets for anti-cancer and immunotherapy because their abnormal regulation can result in cancer development and autoimmune diseases.
TBK1 demonstrates multiple functions in cancer biology through its effects on cell survival mechanisms and anti-apoptotic pathways as well as immune evasion and metabolic processes. The development of targeted TBK1 treatments represents a key research area in cancer therapy with combined treatment approaches anticipated to address drug resistance while boosting immunotherapy outcomes. TBK1 functions differently across various cancer types and requires additional research to clarify its precise molecular mechanisms and its value in clinical applications.
References
- Runde, A., et al. The role of TBK1 in cancer pathogenesis and anticancer immunity. Journal of Experimental & Clinical Cancer Research. 2022, 41(1): 135.
- Hu, L., et al. Mechanism of TBK1 activation in cancer cells. Cell Insight. 2024: 100197.
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