Characterization of kinase inhibitors using different phosphorylation states of colony stimulating factor-1 receptor tyrosine kinase

Kitagawa, Daisuke; Gouda, Masaki; Kirii, Yasuyuki; Sugiyama, Naoyuki; Ishihama, Yasushi; Fujii, Ikuo; Narumi, Yugo; Akita, Kensaku; Yokota, Koichi

doi:10.1093/jb/mvr112

Cited by 19 publications

(11 citation statements)

References 58 publications

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“…This may include the polarization of TAM, as inhibition of NF‐κB in TAM has been reported to induce antitumoral immune responses 23. Sorafenib targets, such as the CSF‐receptor‐1,24 MAPKp38,12 and JAK/STAT,25 which are pivotal for Mϕ maturation, support this finding 26‐28. Sorafenib‐mediated cytokine induction in polarized Mϕ might therefore rely on complex signaling networks.…”

Section: Discussionmentioning

confidence: 86%

Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells

Sprinzl¹,

Reisinger²,

Puschnik³

et al. 2013

Hepatology

151

116

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Alternatively polarized macrophages (MU) shape the microenvironment of hepatocellular carcinoma (HCC) and temper anticancer immune responses. We investigated if sorafenib alters the HCC microenvironment by restoring classical macrophage polarization and triggering tumor-directed natural killer (NK) cell responses. In vivo experiments were conducted with sorafenib (25 mg/kg)-treated C57BL/6 wildtype as well as hepatitis B virus (HBV) and lymphotoxin transgenic mice with and without HCC. Monocyte-derived MU or tumor-associated macrophages (TAM) isolated from HCC tissue were treated with sorafenib (0.07-5.0 lg/mL) and cocultured with autologous NK cells. MU and NK cell activation was analyzed by flow cytometry and killing assays, respectively. Cytokine and growth factor release was measured by enzyme-linked immunosorbent assay. Short-term administration of sorafenib triggered activation of hepatic NK cells in wildtype and tumor-bearing mice. In vitro, sorafenib sensitized MU to lipopolysaccharide, reverted alternative MU polarization and enhanced IL12 secretion (P 5 0.0133). NK cells activated by sorafenib-treated MU showed increased degranulation (15.3 6 0.2% versus 32.0 6 0.9%, P < 0.0001) and interferon-gamma (IFN-c) secretion (2.1 6 0.2% versus 8.0 6 0.2%, P < 0.0001) upon target cell contact. Sorafenib-triggered NK cell activation was verified by coculture experiments using TAM. Sorafenib-treated MU increased cytolytic NK cell function against K562, Raji, and HepG2 target cells in a dose-dependent manner. Neutralization of interleukin (IL)12 or IL18 as well as inhibition of the nuclear factor kappa B (NF-jB) pathway reversed NK cell activation in MU/NK cocultures. Conclusion: Sorafenib triggers proinflammatory activity of TAM and subsequently induces antitumor NK cell responses in a cytokine-and NF-jB-dependent fashion. This observation is relevant for HCC therapy, as sorafenib is a compound in clinical use that reverts alternative polarization of TAM in HCC. (HEPATOLOGY 2013;57:2358-2368 T umor-associated macrophages (TAM) located in the hepatocellular carcinoma (HCC) environment increase HCC recurrence after resection and reduce patient survival. 1,2 TAM thereby fosters tumor cell proliferation and tumor spread. 3 Natural killer (NK) cell numbers and activity, on the other hand, are associated with lower HCC stages and improved patient survival. 4,5 An outstanding feature of Abbreviations: AFP, alpha-fetoprotein; C57BL/6 wt , C57BL/6

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Section: Discussionmentioning

confidence: 86%

Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells

Sprinzl¹,

Reisinger²,

Puschnik³

et al. 2013

Hepatology

151

116

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“…) and FMS (Kitagawa et al . ), indicating that the type I (ATP‐competitive) kinase inhibitors binds preferentially inactive form of some kinases. A concurrent profiling assay using inactive kinases may be advisable to generate comprehensive data regarding compound affinity for targets.…”

Section: Discussionmentioning

confidence: 99%

“…Generally, imatinib and nilotinib are classified as inhibitors of inactive kinases (type II inhibitors), in contrast to sunitinib, which is an inhibitor of active kinases (type I inhibitor). Sunitinib, however, has demonstrated to have high affinity to a members of the PDGFR family kinases and bind preferentially to the inactive forms of KIT (Quintas-Cardama & Cortes 2008;Gajiwala et al 2009) and FMS (Kitagawa et al 2012), indicating that the type I (ATP-competitive) kinase inhibitors binds preferentially inactive form of some kinases. A concurrent profiling assay using inactive kinases may be advisable to generate comprehensive data regarding compound affinity for targets.…”

Section: Figurementioning

confidence: 99%

Activity‐based kinase profiling of approved tyrosine kinase inhibitors

Kitagawa¹,

Yokota²,

Gouda³

et al. 2012

Genes to Cells

183

162

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The specificities of nine approved tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, and pazopanib) were determined by activity-based kinase profiling using a large panel of human recombinant active kinases. This panel consisted of 79 tyrosine kinases, 199 serine/threonine kinases, three lipid kinases, and 29 disease-relevant mutant kinases. Many potential targets of each inhibitor were identified by kinase profiling at the K m for ATP. In addition, profiling at a physiological ATP concentration (1 mM) was carried out, and the IC 50 values of the inhibitors against each kinase were compared with the estimated plasma-free concentration (calculated from published pharmacokinetic parameters of plasma C trough and C max values). This analysis revealed that the approved kinase inhibitors were well optimized for their target kinases. This profiling also implicates activity at particular off-target kinases in drug side effects. Thus, large-scale kinase profiling at both K m and physiological ATP concentrations could be useful in characterizing the targets and off-targets of kinase inhibitors.

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“…Enzymatic activity of TNIK was measured by mobility shift assay52 using a QuickScout Screening Assist Kit (07-138MS, Carna Biosciences). The reaction product was quantified using a LabChip EZ Reader II (PerkinElmer).…”

Section: Methodsmentioning

confidence: 99%

TNIK inhibition abrogates colorectal cancer stemness

Masuda¹,

Uno²,

Ohbayashi³

et al. 2016

Nat Commun

133

158

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Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik−/−/Apcmin/+ mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apcmin/+ mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach.

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Characterization of kinase inhibitors using different phosphorylation states of colony stimulating factor-1 receptor tyrosine kinase

Cited by 19 publications

References 58 publications

Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells

Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells

Activity‐based kinase profiling of approved tyrosine kinase inhibitors

TNIK inhibition abrogates colorectal cancer stemness

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