Skip to main content

Advertisement

SpringerLink
Log in

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

  • Review
  • Published:
Journal of Cell Communication and Signaling Aims and scope

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

AALE:

Immortalized tracheobronchial epithelial cells

AKT:

Protein kinase B

BRAFi:

BRAF inhibitor

CCL5:

Chemokine ligand 5

CEP1:

Centrosomal protein 170

DC:

Dendritic cell

DKO:

Dendritic cell knockout

EMT:

Epithelial-to-mesenchymal transition

GEMM:

Genetically engineered mouse model

GFP:

Green fluorescent protein

IFN-I:

Type I interferon

IFN-β:

Interferon β

IFNAR1:

Interferon alpha/beta receptor 1

IKB:

Inhibitor of NFκβ

IKK:

Iκβ kinase

IL1:

Interleukin 1

IL6:

Interleukin 6

IRF3:

Interferon regulator factor 3

LATS1:

Large tumor suppressor kinase 1

LC3:

Microtubule-associated protein-1 light chain 3

MEFs:

Mouse embryonic fibroblasts

MEKi:

MEK inhibitor

mTOR:

Mammalian target of rapamycin

NFκβ:

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

NSCLC:

Non-small cell lung cancer

NSG:

NOD scid gamma

NUMA:

Nuclear mitotic apparatus protein

OPTN:

Optineurin

PD-1:

Programmed cell death protein 1

PDA:

Pancreatic ductal adenocarcinoma

PDK1:

3-phosphoinositide-dependent protein kinase-1

PLK1:

Polo-like kinase 1

RAL:

Ras-related protein

RAS:

Rat sarcoma virus

S6K:

p70 S6 kinase

SILAC:

Stable isotope labeling by amino acids in cell culture

siRNA:

Small interfering RNA

STAT3:

Signal transducer and activator of transcription 3

STING:

Stimulator of interferon genes

TANK:

TRAF family member associated NF-κβ activator

TBK1:

TANK -binding kinase 1

TBK1i:

TBK1 inhibitor

TCGA:

The cancer genome atlas

TGFB:

Transforming growth factor β

WT:

Wild-type

YAP1:

Yes associated protein 1

References

  • 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):108–112

  • 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):436–446

    Article  CAS  PubMed  Google Scholar 

  • 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):961–975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):157–170

  • 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):5077–5094

    CAS  PubMed  Google Scholar 

  • 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):1018–1030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):832–851

    Article  CAS  PubMed  Google Scholar 

  • Fimia GM, Kroemer G, Piacentini M (2013) Molecular mechanisms of selective autophagy. Cell Death Differ 20(1):1–2

    Article  CAS  PubMed  Google Scholar 

  • 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.e1194

    Article  Google Scholar 

  • 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):460–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1230–1237

    Article  CAS  PubMed  Google Scholar 

  • 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):1271–1285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishikawa H, Barber GN (2008) STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455(7213):674–678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jo EK, Yuk JM, Shin DM, Sasakawa C (2013) Roles of autophagy in elimination of intracellular bacterial pathogens. Front Immunol 4:97

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):12414–12419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6(4):463–477

    Article  CAS  PubMed  Google Scholar 

  • 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):9378–9383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1171–1180

    Article  CAS  PubMed  Google Scholar 

  • 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):e50672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.e157

    Article  Google Scholar 

  • 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):458–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 6:10072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):223–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reggiori F, Komatsu M, Finley K, Simonsen A (2012) Autophagy: more than a nonselective pathway. Int J Cell Biol 2012:219625

    PubMed  PubMed Central  Google Scholar 

  • 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):313–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):296–300

    Article  CAS  PubMed  Google Scholar 

  • Vu HL, Aplin AE (2014) Targeting TBK1 inhibits migration and resistance to MEK inhibitors in mutant NRAS melanoma. Mol Cancer Res 12(10):1509–1519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):228–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):830–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1493–1507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):717–729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):520–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):452–465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Cancer Biology Graduate Program, Hamon Center for Therapeutic Oncology Research and Department of Surgery, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX, 75390-8593, USA

    Victoria H. Cruz & Rolf A. Brekken

  2. Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USA

    Rolf A. Brekken

Authors
  1. Victoria H. Cruz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rolf A. Brekken
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rolf A. Brekken.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cruz, V.H., Brekken, R.A. Assessment of TANK-binding kinase 1 as a therapeutic target in cancer. J. Cell Commun. Signal. 12, 83–90 (2018). https://doi.org/10.1007/s12079-017-0438-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12079-017-0438-y

Keywords

Search

Navigation