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Research ArticleArticle

Off-Target Serine/Threonine Kinase 10 Inhibition by Erlotinib Enhances Lymphocytic Activity Leading to Severe Skin Disorders

Naoko Yamamoto, Masashi Honma and Hiroshi Suzuki
Molecular Pharmacology September 2011, 80 (3) 466-475; DOI: https://doi.org/10.1124/mol.110.070862
Naoko Yamamoto
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Masashi Honma
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Hiroshi Suzuki
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Abstract

Skin disorders are among the most common adverse events related to treatment with epidermal growth factor receptor (EGFR) kinase inhibitors, and of these, erlotinib is known to cause more frequent and severe skin disease than other agents in this class. Although previous reports have shown that cutaneous manifestations are triggered by the inhibition of multiple EGFR-related homeostatic functions of the skin, this mechanism alone cannot explain the differences in frequency and severity of skin disorders caused by different kinase inhibitors. In this study, we focused on the relationship between the off-target kinase inhibition and aggravation of skin disorders. Based on calculations using reported Kd values and plasma drug concentrations, serine/threonine kinase 10 (STK10) and Ste20-like kinase (SLK) were selected as candidates preferentially inhibited by erlotinib over gefitinib. In vitro experiments confirmed that STK10 and SLK kinase activity are inhibited by erlotinib at clinical concentrations, whereas only STK10 is slightly inhibited by gefitinib. It was also shown that erlotinib up-regulated lymphocytic responses such as interleukin (IL)-2 secretion and cell migration at clinical concentrations, whereas gefitinib did not affect lymphocyte activity. Moreover, small interfering RNA experiments revealed that STK10 plays a major role in up-regulation of the lymphocytic responses induced by erlotinib treatment. Finally, the role of erlotinib-induced lymphocyte activation was assessed in vivo using irritant hypersensitivity models. The results indicated that erlotinib aggravates cutaneous inflammatory reactions through the activation of lymphocytic responses such as IL-2 secretion and cell migration. These results demonstrated that off-target inhibition of STK10 by erlotinib enhances lymphocytic responses, which lead to the aggravation of skin inflammation.

Footnotes

  • This work was supported in part by Grant-in-Aid for Scientific Research [Grant 21390041] and Grant-in-Aid for Scientific Research on Innovative Areas HD-Physiology [Grant 22136015] from the Ministry of Education, Science, and Culture of Japan.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.070862.

  • ABBREVIATIONS:

    EGFR
    epidermal growth factor receptor
    FBS
    fetal bovine serum
    GAK
    cyclin G-associated kinase
    MEK1
    mitogen-activated protein kinase extracellular signal-regulated kinase kinase-1
    PMA
    phorbol 12-myristate 13-acetate
    SDF-1
    stromal cell-derived factor-1
    SLK
    Ste20-like kinase
    STK10
    serine/threonine kinase 10
    IL
    interleukin
    PCR
    polymerase chain reaction
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    ERK
    extracellular signal-regulated kinase
    TCR
    T-cell receptor
    siRNA
    small interfering RNA
    FTY720
    2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol, hydrochloride
    RNAi
    RNA interference
    PD98059
    2′-amino-3′-methoxyflavone.

  • Received December 23, 2010.
  • Accepted May 23, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (3)
Molecular Pharmacology
Vol. 80, Issue 3
1 Sep 2011
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Research ArticleArticle

Off-Target Serine/Threonine Kinase 10 Inhibition by Erlotinib Enhances Lymphocytic Activity Leading to Severe Skin Disorders

Naoko Yamamoto, Masashi Honma and Hiroshi Suzuki
Molecular Pharmacology September 1, 2011, 80 (3) 466-475; DOI: https://doi.org/10.1124/mol.110.070862

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Research ArticleArticle

Off-Target Serine/Threonine Kinase 10 Inhibition by Erlotinib Enhances Lymphocytic Activity Leading to Severe Skin Disorders

Naoko Yamamoto, Masashi Honma and Hiroshi Suzuki
Molecular Pharmacology September 1, 2011, 80 (3) 466-475; DOI: https://doi.org/10.1124/mol.110.070862
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