Non-canonical IKKs, IKKϵ and TBK1, as novel therapeutic targets in the treatment of non-small cell lung cancer

Kim, Jae-Young; Beg, Amer A.; Haura, Eric B.

doi:10.1517/14728222.2013.833188

Cited by 13 publications

(11 citation statements)

References 21 publications

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“…Identifying specific biomarkers for patient selection and for effective pathway inhibition is a key for the development of targeted therapeutics. With this in mind, we evaluated the role of TBK1, a noncanonical IKK, which has been reported to be an important kinase in cancer (4). TBK1 inhibition in a panel of 79 cancer cell lines (35 KRAS-mutant and 18 KRAS-wt, confirmed by CCLE) was achieved using small-molecule inhibitors as well as shRNAs to knockdown TBK1; however, we did not observe consistent growth reduction in vitro.…”

Section: Discussionmentioning

confidence: 91%

“…Besides its key role in innate immune response, increasing evidence indicates that the activation of TBK1 and its close homolog IKKe is associated with the development of human cancers (2)(3)(4)(5)(6)(7)(8)(9)(10). TBK1 is an 84 kDa, 729 amino acid-long protein containing an N-terminal kinase domain, a ubiquitin-like domain and two C-terminal coiled-coil domains.…”

Section: Introductionmentioning

confidence: 99%

“…Although the role of TBK1 in cancer still remains unclear, recent studies suggested its role in regulation of cell growth and proliferation, and oncogenic transformation (2,4,9). Shen and Hahn (1) first demonstrated the role of both TBK1 and IKKe in cell transformation.…”

Section: Introductionmentioning

confidence: 99%

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Evaluating TBK1 as a Therapeutic Target in Cancers with Activated IRF3

Muvaffak¹,

Pan²,

Yan³

et al. 2014

Molecular Cancer Research

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TBK1 (TANK-binding kinase 1) is a noncanonical IkB protein kinase that phosphorylates and activates downstream targets such as IRF3 and c-Rel and, mediates NF-kB activation in cancer. Previous reports demonstrated synthetic lethality of TBK1 with mutant KRAS in non-small cell lung cancer (NSCLC); thus, TBK1 could be a novel target for treatment of KRAS-mutant NSCLC. Here, the effect of TBK1 on proliferation in a panel of cancer cells by both genetic and pharmacologic approaches was evaluated. In KRAS-mutant cancer cells, reduction of TBK1 activity by knockdown or treatment with TBK1 inhibitors did not correlate with reduced proliferation in a two-dimensional viability assay. Verification of target engagement via reduced phosphorylation of S386 of IRF3 (pIRF3 S386 ) was difficult to assess in NSCLC cells due to low protein expression. However, several cell lines were identified with high pIRF3 S386 levels after screening a large panel of cell lines, many of which also harbor KRAS mutations. Specifically, a large subset of KRAS-mutant pancreatic cancer cell lines was uncovered with high constitutive pIRF3 S386 levels, which correlated with high levels of phosphorylated S172 of TBK1 (pTBK1 S172 ).Finally, TBK1 inhibitors dose-dependently inhibited pIRF3 S386 in these cell lines, but this did not correlate with inhibition of cell growth. Taken together, these data demonstrate that the regulation of pathways important for cell proliferation in some NSCLC, pancreatic, and colorectal cell lines is not solely dependent on TBK1 activity.Implications: TBK1 has therapeutic potential under certain contexts and phosphorylation of its downstream target IRF3 is a biomarker of TBK1 activity.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Evaluating TBK1 as a Therapeutic Target in Cancers with Activated IRF3

Muvaffak¹,

Pan²,

Yan³

et al. 2014

Molecular Cancer Research

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“…1,20,21 Although TBK1 was proposed as a target in various cancer types and particularly in facilitating EMT processes, its associated tumor biology to large extent remains unclear. 9,22 Therefore, tool compounds for deciphering TBK1 biology as well as specific inhibitors are needed to more deeply investigate its function with respect to the orchestrated network of cellular signaling of the antiviral response, as well as its role in cancer progression and metastasis.…”

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confidence: 99%

Identification and Further Development of Potent TBK1 Inhibitors

et al. 2014

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The cytosolic Ser/Thr kinase TBK1 was discovered to be an essential element in the mediation of signals that lead to tumor migration and progression. These findings meet the need for the identification of novel tool compounds and potential therapeutics to gain deeper insights into TBK1 related signaling and its relevance in tumor progression. Herein, we undertake the activity-based screening for unique inhibitors of TBK1 and their subsequent optimization. Initial screening approaches identified a selection of TBK1 inhibitors that were optimized using methods of medicinal chemistry. Variations of the structural characteristics of a representative 2,4,6-substituted pyrimidine scaffold resulted in improved potency. Prospective use as tool compounds or basic contributions to drug design approaches are anticipated for our improved small molecules.

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“…IKK-related kinases, namely TBK1 (TANK binding kinase) and IKKε (inhibitor of κB kinase epsilon), have been associated with the development of numerous cancers in tissues from ovarian, breast, lung, colorectal, prostate, skin, nerve, and pancreatic origin (Hsu et al, 2012;Barbie et al, 2014;Challa et al, 2016;Göktuna et al, 2016;Zubair et al, 2016;Lu et al, 2017;Péant et al, 2017). As a result, TBK1 and IKKε have emerged as potential targets for cancer therapy in many malignancies (Kim et al, 2013;Niederberger et al, 2013). Accumulating evidence supports that IKK-related kinases orchestrate tumor cell survival upon genotoxic stress by the direct regulation of the master regulators of cell survival like AKT and NF-κB (Chau et al, 2008;Guo et al, 2011;Xie et al, 2011).…”

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confidence: 99%

IKBKE inhibits TSC1 to activate the mTOR/S6K pathway for oncogenic transformation

Göktuna¹

2018

Turk J Biol

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Introduction mTOR is a serine/threonine kinase and component of two distinct multiprotein complexes called mTORC1 and 2 (mTOR complex 1 and 2). mTORC1 is composed of mTOR, Raptor (RPTOR, regulatory-associated protein of mTOR), mLST8 (mTOR associated protein, LST8 homolog), DEPTOR (DEP domain containing mTOR interacting protein), and Pras40 (a.k.a. AKT1S1, prolinerich Akt substrate 40kDa). mTORC1 can be inhibited by rapamycin (Laplante and Sabatini, 2012; AlQurashi et al., 2013). mTORC2 is composed of mTOR, Rictor (RPTOR independent companion of mTOR complex 2), mLST8, MAPKAP1 (a.k.a. Sin1, mitogen-activated protein kinase associated protein 1), PRR5/Protor-1 (proline rich 5 like), and DEPTOR. mTOR can receive signals from diverse upstream factors, such as growth factors, energy sources, stress, and other metabolites, to control major cellular machinery in cell growth, autophagy, protein synthesis, and lipid biosynthesis (Laplante and Sabatini, 2012; Saxton and Sabatini, 2017). Aberrant mTOR activation is observed in many diseases such as cancer, cardiovascular disease, and diabetes (Dowling et al., 2010). mTORC1 complexes can also be negatively regulated by upstream signals from hypoxia, low ATP levels, or genotoxic stress, which in turn activate inhibitory proteins such as AMPK (5' AMP-activated protein kinase) or TSC1/2 (tuberous sclerosis 1 and 2) (AlQurashi et al., 2013). TSC1/2 heterodimers are especially important in inhibiting mTORC1 activity upon stress signals (Inoki et al., 2005). Mechanistically, TSC1/2 inactivate mTORC1 by converting GTP-bound active Rheb (Ras homolog enriched in brain), an essential component for mTORC1 activity, to its GDP-bound inactive form (Inoki et al., 2003a). Regulation of TSC1/2 activity involves transmission of various growth signals (RTKs, Wnt, etc.), which eventually stimulate central signaling hubs, such as PI3K and Ras proteins, to activate oncogenic PI3K/Akt or Ras/RAF/MAPK signaling cascades (Saxton and Sabatini, 2017). These signaling cascades, in turn, promote the activation of downstream effectors such as AKT (serine/ Abstract: IKBKE (IKKε) has emerged as a key modulator of multiple substrates, controlling oncogenic pathways in various malignancies. mTOR signaling, required for cellular growth, proliferation, and vascular angiogenesis in cancer, is potentially one of the pathways regulated by IKKε. Upon activation by various stimuli, PI3K/AKT or similar effectors can relieve the inhibitory effect of the TSC1/TSC2 complex through their phosphorylation to favor mTOR/S6K activation in the downstream. Therefore, any activity that interferes with PI3K/AKT or their downstream targets, such as TSC1/2 or GSK3α/β, may activate the mTOR/S6K pathway for oncogenic transformation in normal cells. Previous studies have shown that PI3K/AKT can be directly phosphoregulated by IKKε. Here, we propose a new regulatory function for IKKε in the mTOR/S6K pathway through its direct interaction with TSC1, leading to TSC1 phosphorylation, which is vital to suppress its inhibitory role in mT...

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Non-canonical IKKs, IKKϵ and TBK1, as novel therapeutic targets in the treatment of non-small cell lung cancer

Cited by 13 publications

References 21 publications

Evaluating TBK1 as a Therapeutic Target in Cancers with Activated IRF3

Evaluating TBK1 as a Therapeutic Target in Cancers with Activated IRF3

Identification and Further Development of Potent TBK1 Inhibitors

IKBKE inhibits TSC1 to activate the mTOR/S6K pathway for oncogenic transformation

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