Assessment of TANK-binding kinase 1 as a therapeutic target in cancer

  • Victoria H. Cruz
  • Rolf A. BrekkenEmail author


TANK-binding kinase 1 (TBK1) is central to multiple biological processes that promote tumorigenesis including cell division, autophagy, innate immune response and AKT-pro survival signaling. TBK1 is well studied and most known for its function in innate immunity. However, the serine threonine protein kinase received significant attention as a synthetic lethal partner and effector of the major oncogene, RAS. This review summarizes newly identified cancer promoting functions of TBK1 and evaluates the therapeutic potential of targeting TBK1 in cancer.


Autophagy Cancer therapeutic target Pancreatic cancer RAS TBK1 



Immortalized tracheobronchial epithelial cells


Protein kinase B


BRAF inhibitor


Chemokine ligand 5


Centrosomal protein 170


Dendritic cell


Dendritic cell knockout


Epithelial-to-mesenchymal transition


Genetically engineered mouse model


Green fluorescent protein


Type I interferon


Interferon β


Interferon alpha/beta receptor 1


Inhibitor of NFκβ


Iκβ kinase


Interleukin 1


Interleukin 6


Interferon regulator factor 3


Large tumor suppressor kinase 1


Microtubule-associated protein-1 light chain 3


Mouse embryonic fibroblasts


MEK inhibitor


Mammalian target of rapamycin


Nuclear factor kappa-light-chain-enhancer of activated B cells


Non-small cell lung cancer


NOD scid gamma


Nuclear mitotic apparatus protein




Programmed cell death protein 1


Pancreatic ductal adenocarcinoma


3-phosphoinositide-dependent protein kinase-1


Polo-like kinase 1


Ras-related protein


Rat sarcoma virus


p70 S6 kinase


Stable isotope labeling by amino acids in cell culture


Small interfering RNA


Signal transducer and activator of transcription 3


Stimulator of interferon genes


TRAF family member associated NF-κβ activator


TANK -binding kinase 1


TBK1 inhibitor


The cancer genome atlas


Transforming growth factor β




Yes associated protein 1



The authors thank Drs. Jonathan Cooper and Aubhishek Zaman for many helpful discussions and members of the Brekken lab for critical review of this manuscript. We also gratefully acknowledge Dr. Tae Hyun Hwang for his help with TCGA gene expression analysis and Dave Primm for editorial assistance.


  1. Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, Schinzel AC, Sandy P, Meylan E, Scholl C, Frohling S, Chan EM, Sos ML, Michel K, Mermel C, Silver SJ, Weir BA, Reiling JH, Sheng Q, Gupta PB, Wadlow RC, Le H, Hoersch S, Wittner BS, Ramaswamy S, Livingston DM, Sabatini DM, Meyerson M, Thomas RK, Lander ES, Mesirov JP, Root DE, Gilliland DG, Jacks T. and Hahn WC (2009) "Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1." Nature 462(7269):108–112Google Scholar
  2. Chen H, Sun H, You F, Sun W, Zhou X, Chen L, Yang J, Wang Y, Tang H, Guan Y, Xia W, Gu J, Ishikawa H, Gutman D, Barber G, Qin Z, Jiang Z (2011) Activation of STAT6 by STING is critical for antiviral innate immunity. Cell 147(2):436–446CrossRefPubMedGoogle Scholar
  3. Chiang SH, Bazuine M, Lumeng CN, Geletka LM, Mowers J, White NM, Ma JT, Zhou J, Qi N, Westcott D, Delproposto JB, Blackwell TS, Yull FE, Saltiel AR (2009) The protein kinase IKKepsilon regulates energy balance in obese mice. Cell 138(5):961–975CrossRefPubMedPubMedCentralGoogle Scholar
  4. Chien Y, Kim S, Bumeister R, Loo YM, Kwon SW, Johnson CL, Balakireva MG, Romeo Y, Kopelovich L, Gale M, Yeaman C, Camonis JH, Zhao Y and White MA (2006) RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell 127(1):157–170Google Scholar
  5. Cooper JM, Ou YH, McMillan EA, Vaden RM, Zaman A, Bodemann BO, Makkar G, Posner BA, White MA (2017) TBK1 provides context-selective support of the activated AKT/mTOR pathway in lung cancer. Cancer Res 77(18):5077–5094PubMedGoogle Scholar
  6. Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE, Katibah GE, Woo SR, Lemmens E, Banda T, Leong JJ, Metchette K, Dubensky TW Jr, Gajewski TF (2015) Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep 11(7):1018–1030CrossRefPubMedPubMedCentralGoogle Scholar
  7. Eskiocak B, McMillan EA, Mendiratta S, Kollipara RK, Zhang H, Humphries CG, Wang C, Garcia-Rodriguez J, Ding M, Zaman A, Rosales TI, Eskiocak U, Smith MP, Sudderth J, Komurov K, Deberardinis RJ, Wellbrock C, Davies MA, Wargo JA, Yu Y, De Brabander JK, Williams NS, Chin L, Rizos H, Long GV, Kittler R, White MA (2017) Biomarker accessible and chemically addressable mechanistic subtypes of braf melanoma. Cancer Discov 7(8):832–851CrossRefPubMedGoogle Scholar
  8. Fimia GM, Kroemer G, Piacentini M (2013) Molecular mechanisms of selective autophagy. Cell Death Differ 20(1):1–2CrossRefPubMedGoogle Scholar
  9. Gukovsky I, Li N, Todoric J, Gukovskaya A, Karin M (2013) Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer. Gastroenterology 144(6):1199.e1194–1209.e1194CrossRefGoogle Scholar
  10. Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V, Coller HA, Dipaola RS, Gelinas C, Rabinowitz JD, White E (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 25(5):460–470CrossRefPubMedPubMedCentralGoogle Scholar
  11. Helgason E, Phung QT, Dueber EC (2013) Recent insights into the complexity of Tank-binding kinase 1 signaling networks: the emerging role of cellular localization in the activation and substrate specificity of TBK1. FEBS Lett 587(8):1230–1237CrossRefPubMedGoogle Scholar
  12. Hugo W, Shi H, Sun L, Piva M, Song C, Kong X, Moriceau G, Hong A, Dahlman KB, Johnson DB, Sosman JA, Ribas A, Lo RS (2015) Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 162(6):1271–1285CrossRefPubMedPubMedCentralGoogle Scholar
  13. Ishikawa H, Barber GN (2008) STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455(7213):674–678CrossRefPubMedPubMedCentralGoogle Scholar
  14. Jo EK, Yuk JM, Shin DM, Sasakawa C (2013) Roles of autophagy in elimination of intracellular bacterial pathogens. Front Immunol 4:97CrossRefPubMedPubMedCentralGoogle Scholar
  15. Kim JY, Welsh EA, Oguz U, Fang B, Bai Y, Kinose F, Bronk C, Remsing Rix LL, Beg AA, Rix U, Eschrich SA, Koomen JM, Haura EB (2013) Dissection of TBK1 signaling via phosphoproteomics in lung cancer cells. Proc Natl Acad Sci U S A 110(30):12414–12419CrossRefPubMedPubMedCentralGoogle Scholar
  16. Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6(4):463–477CrossRefPubMedGoogle Scholar
  17. Ma X, Helgason E, Phung QT, Quan CL, Iyer RS, Lee MW, Bowman KK, Starovasnik MA, Dueber EC (2012) Molecular basis of tank-binding kinase 1 activation by transautophosphorylation. Proc Natl Acad Sci U S A 109(24):9378–9383CrossRefPubMedPubMedCentralGoogle Scholar
  18. Marchlik E, Thakker P, Carlson T, Jiang Z, Ryan M, Marusic S, Goutagny N, Kuang W, Askew GR, Roberts V, Benoit S, Zhou T, Ling V, Pfeifer R, Stedman N, Fitzgerald KA, Lin LL, Hall JP (2010) Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality. J Leukoc Biol 88(6):1171–1180CrossRefPubMedGoogle Scholar
  19. Newman AC, Scholefield CL, Kemp AJ, Newman M, McIver EG, Kamal A, Wilkinson S (2012) TBK1 kinase addiction in lung cancer cells is mediated via autophagy of Tax1bp1/Ndp52 and non-canonical NF-kappaB signalling. PLoS ONE 7(11):e50672CrossRefPubMedPubMedCentralGoogle Scholar
  20. Oral EA, Reilly SM, Gomez AV, Meral R, Butz L, Ajluni N, Chenevert TL, Korytnaya E, Neidert AH, Hench R, Rus D, Horowitz JF, Poirier B, Zhao P, Lehmann K, Jain M, Yu R, Liddle C, Ahmadian M, Downes M, Evans RM, Saltiel AR (2017) Inhibition of IKKvarepsilon and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes. Cell Metab 26(1):157.e157–170.e157CrossRefGoogle Scholar
  21. Ou YH, Torres M, Ram R, Formstecher E, Roland C, Cheng T, Brekken R, Wurz R, Tasker A, Polverino T, Tan SL, White MA (2011) TBK1 directly engages Akt/PKB survival signaling to support oncogenic transformation. Mol Cell 41(4):458–470CrossRefPubMedPubMedCentralGoogle Scholar
  22. Pillai S, Nguyen J, Johnson J, Haura E, Coppola D, Chellappan S (2015) Tank binding kinase 1 is a centrosome-associated kinase necessary for microtubule dynamics and mitosis. Nat Commun 6:10072CrossRefPubMedPubMedCentralGoogle Scholar
  23. Pilli M, Arko-Mensah J, Ponpuak M, Roberts E, Master S, Mandell MA, Dupont N, Ornatowski W, Jiang S, Bradfute SB, Bruun JA, Hansen TE, Johansen T, Deretic V (2012) TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation. Immunity 37(2):223–234CrossRefPubMedPubMedCentralGoogle Scholar
  24. Reggiori F, Komatsu M, Finley K, Simonsen A (2012) Autophagy: more than a nonselective pathway. Int J Cell Biol 2012:219625PubMedPubMedCentralGoogle Scholar
  25. Reilly SM, Chiang SH, Decker SJ, Chang L, Uhm M, Larsen MJ, Rubin JR, Mowers J, White NM, Hochberg I, Downes M, Yu RT, Liddle C, Evans RM, Oh D, Li P, Olefsky JM, Saltiel AR (2013) An inhibitor of the protein kinases TBK1 and IKK-varepsilon improves obesity-related metabolic dysfunctions in mice. Nat Med 19(3):313–321CrossRefPubMedPubMedCentralGoogle Scholar
  26. Rosenfeldt MT, O'Prey J, Morton JP, Nixon C, MacKay G, Mrowinska A, Au A, Rai TS, Zheng L, Ridgway R, Adams PD, Anderson KI, Gottlieb E, Sansom OJ, Ryan KM (2013) p53 status determines the role of autophagy in pancreatic tumour development. Nature 504(7479):296–300CrossRefPubMedGoogle Scholar
  27. Vu HL, Aplin AE (2014) Targeting TBK1 inhibits migration and resistance to MEK inhibitors in mutant NRAS melanoma. Mol Cancer Res 12(10):1509–1519CrossRefPubMedPubMedCentralGoogle Scholar
  28. Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV, Brady NR, Richter B, Korac J, Waidmann O, Choudhary C, Dotsch V, Bumann D, Dikic I (2011) Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333(6039):228–233CrossRefPubMedPubMedCentralGoogle Scholar
  29. Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MY, Duggan R, Wang Y, Barber GN, Fitzgerald KA, Alegre ML, Gajewski TF (2014) STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41(5):830–842CrossRefPubMedPubMedCentralGoogle Scholar
  30. Xiao Y, Zou Q, Xie X, Liu T, Li HS, Jie Z, Jin J, Hu H, Manyam G, Zhang L, Cheng X, Wang H, Marie I, Levy DE, Watowich SS, Sun SC (2017) The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity. J Exp Med 214(5):1493–1507CrossRefPubMedPubMedCentralGoogle Scholar
  31. Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, Bause A, Li Y, Stommel JM, Dell'antonio G, Mautner J, Tonon G, Haigis M, Shirihai OS, Doglioni C, Bardeesy N, Kimmelman AC (2011) Pancreatic cancers require autophagy for tumor growth. Genes Dev 25(7):717–729CrossRefPubMedPubMedCentralGoogle Scholar
  32. Yang S, Imamura Y, Jenkins RW, Canadas I, Kitajima S, Aref A, Brannon A, Oki E, Castoreno A, Zhu Z, Thai T, Reibel J, Qian Z, Ogino S, Wong KK, Baba H, Kimmelman AC, Pasca Di Magliano M, Barbie DA (2016) Autophagy inhibition dysregulates TBK1 signaling and promotes pancreatic inflammation. Cancer Immunol Res 4(6):520–530CrossRefPubMedPubMedCentralGoogle Scholar
  33. Zhu Z, Aref AR, Cohoon TJ, Barbie TU, Imamura Y, Yang S, Moody SE, Shen RR, Schinzel AC, Thai TC, Reibel JB, Tamayo P, Godfrey JT, Qian ZR, Page AN, Maciag K, Chan EM, Silkworth W, Labowsky MT, Rozhansky L, Mesirov JP, Gillanders WE, Ogino S, Hacohen N, Gaudet S, Eck MJ, Engelman JA, Corcoran RB, Wong KK, Hahn WC, Barbie DA (2014) Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discov 4(4):452–465CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The International CCN Society 2017

Authors and Affiliations

  1. 1.Cancer Biology Graduate Program, Hamon Center for Therapeutic Oncology Research and Department of SurgeryUT Southwestern Medical CenterDallasUSA
  2. 2.Department of PharmacologyUT Southwestern Medical CenterDallasUSA

Personalised recommendations