Sorafenib inhibits many kinase mutations associated with drug-resistant gastrointestinal stromal tumors

Michael Heinrich, Adrian Marino-Enriquez, Ajia Presnell, Rachel S. Donsky, Diana J. Griffith, Arin McKinley, Janice Patterson, Takahiro Taguchi, Cher Wei Liang, Jonathan A. Fletcher

    Research output: Contribution to journalArticle

    41 Citations (Scopus)

    Abstract

    Sorafenib has substantial clinical activity as third- or fourth-line treatment of imatinib- and sunitinib-resistant gastrointestinal stromal tumors (GIST). Because sorafenib targets both angiogenesis-related kinases (VEGFR) and the pathogenetic kinases found in GIST (KIT or PDGFRA), the molecular basis for sorafenib efficacy in this setting remains unknown. We sought to determine the spectrum of activity of sorafenib against different mutant kinases associated with drug-sensitive and drug-resistant GIST. We compared the activity of imatinib and sorafenib against transiently expressed mutant forms of KIT and PDGFRA, including various secondary mutations that have been identified in imatinib-resistant or sunitinib-resistant GISTs. We also examined these drugs against four GIST cell lines, three of which are imatinib resistant. In our in vitro studies, we determined that sorafenib inhibited imatinib-resistant mutations in exons encoding the ATP/drug-binding pocket and in exons encoding the activation loop, with the exception of substitutions at KIT codon D816 and PDGFRA codon 842. Notably our data indicate that sorafenib is more effective than imatinib or sunitinib for inhibiting the kinase activity of drug-resistant KIT mutants (as assessed by biochemical IC50). We hypothesize that a major determinant of the efficacy of sorafenib for treatment of advanced GIST is the activity of this agent against KIT or PDGFRA-mutant kinases. These results have implications for the further development of treatments for drug-resistant GIST.

    Original languageEnglish (US)
    Pages (from-to)1770-1780
    Number of pages11
    JournalMolecular Cancer Therapeutics
    Volume11
    Issue number8
    DOIs
    StatePublished - Aug 2012

    Fingerprint

    Gastrointestinal Stromal Tumors
    Phosphotransferases
    Mutation
    Pharmaceutical Preparations
    Codon
    Exons
    sorafenib
    Stromal Cells
    Tumor Cell Line
    Inhibitory Concentration 50
    Imatinib Mesylate
    Adenosine Triphosphate

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Heinrich, M., Marino-Enriquez, A., Presnell, A., Donsky, R. S., Griffith, D. J., McKinley, A., ... Fletcher, J. A. (2012). Sorafenib inhibits many kinase mutations associated with drug-resistant gastrointestinal stromal tumors. Molecular Cancer Therapeutics, 11(8), 1770-1780. https://doi.org/10.1158/1535-7163.MCT-12-0223

    Sorafenib inhibits many kinase mutations associated with drug-resistant gastrointestinal stromal tumors. / Heinrich, Michael; Marino-Enriquez, Adrian; Presnell, Ajia; Donsky, Rachel S.; Griffith, Diana J.; McKinley, Arin; Patterson, Janice; Taguchi, Takahiro; Liang, Cher Wei; Fletcher, Jonathan A.

    In: Molecular Cancer Therapeutics, Vol. 11, No. 8, 08.2012, p. 1770-1780.

    Research output: Contribution to journalArticle

    Heinrich, M, Marino-Enriquez, A, Presnell, A, Donsky, RS, Griffith, DJ, McKinley, A, Patterson, J, Taguchi, T, Liang, CW & Fletcher, JA 2012, 'Sorafenib inhibits many kinase mutations associated with drug-resistant gastrointestinal stromal tumors', Molecular Cancer Therapeutics, vol. 11, no. 8, pp. 1770-1780. https://doi.org/10.1158/1535-7163.MCT-12-0223
    Heinrich, Michael ; Marino-Enriquez, Adrian ; Presnell, Ajia ; Donsky, Rachel S. ; Griffith, Diana J. ; McKinley, Arin ; Patterson, Janice ; Taguchi, Takahiro ; Liang, Cher Wei ; Fletcher, Jonathan A. / Sorafenib inhibits many kinase mutations associated with drug-resistant gastrointestinal stromal tumors. In: Molecular Cancer Therapeutics. 2012 ; Vol. 11, No. 8. pp. 1770-1780.
    @article{99324b4e36094cb0bb07f86cc17293cd,
    title = "Sorafenib inhibits many kinase mutations associated with drug-resistant gastrointestinal stromal tumors",
    abstract = "Sorafenib has substantial clinical activity as third- or fourth-line treatment of imatinib- and sunitinib-resistant gastrointestinal stromal tumors (GIST). Because sorafenib targets both angiogenesis-related kinases (VEGFR) and the pathogenetic kinases found in GIST (KIT or PDGFRA), the molecular basis for sorafenib efficacy in this setting remains unknown. We sought to determine the spectrum of activity of sorafenib against different mutant kinases associated with drug-sensitive and drug-resistant GIST. We compared the activity of imatinib and sorafenib against transiently expressed mutant forms of KIT and PDGFRA, including various secondary mutations that have been identified in imatinib-resistant or sunitinib-resistant GISTs. We also examined these drugs against four GIST cell lines, three of which are imatinib resistant. In our in vitro studies, we determined that sorafenib inhibited imatinib-resistant mutations in exons encoding the ATP/drug-binding pocket and in exons encoding the activation loop, with the exception of substitutions at KIT codon D816 and PDGFRA codon 842. Notably our data indicate that sorafenib is more effective than imatinib or sunitinib for inhibiting the kinase activity of drug-resistant KIT mutants (as assessed by biochemical IC50). We hypothesize that a major determinant of the efficacy of sorafenib for treatment of advanced GIST is the activity of this agent against KIT or PDGFRA-mutant kinases. These results have implications for the further development of treatments for drug-resistant GIST.",
    author = "Michael Heinrich and Adrian Marino-Enriquez and Ajia Presnell and Donsky, {Rachel S.} and Griffith, {Diana J.} and Arin McKinley and Janice Patterson and Takahiro Taguchi and Liang, {Cher Wei} and Fletcher, {Jonathan A.}",
    year = "2012",
    month = "8",
    doi = "10.1158/1535-7163.MCT-12-0223",
    language = "English (US)",
    volume = "11",
    pages = "1770--1780",
    journal = "Molecular Cancer Therapeutics",
    issn = "1535-7163",
    publisher = "American Association for Cancer Research Inc.",
    number = "8",

    }

    TY - JOUR

    T1 - Sorafenib inhibits many kinase mutations associated with drug-resistant gastrointestinal stromal tumors

    AU - Heinrich, Michael

    AU - Marino-Enriquez, Adrian

    AU - Presnell, Ajia

    AU - Donsky, Rachel S.

    AU - Griffith, Diana J.

    AU - McKinley, Arin

    AU - Patterson, Janice

    AU - Taguchi, Takahiro

    AU - Liang, Cher Wei

    AU - Fletcher, Jonathan A.

    PY - 2012/8

    Y1 - 2012/8

    N2 - Sorafenib has substantial clinical activity as third- or fourth-line treatment of imatinib- and sunitinib-resistant gastrointestinal stromal tumors (GIST). Because sorafenib targets both angiogenesis-related kinases (VEGFR) and the pathogenetic kinases found in GIST (KIT or PDGFRA), the molecular basis for sorafenib efficacy in this setting remains unknown. We sought to determine the spectrum of activity of sorafenib against different mutant kinases associated with drug-sensitive and drug-resistant GIST. We compared the activity of imatinib and sorafenib against transiently expressed mutant forms of KIT and PDGFRA, including various secondary mutations that have been identified in imatinib-resistant or sunitinib-resistant GISTs. We also examined these drugs against four GIST cell lines, three of which are imatinib resistant. In our in vitro studies, we determined that sorafenib inhibited imatinib-resistant mutations in exons encoding the ATP/drug-binding pocket and in exons encoding the activation loop, with the exception of substitutions at KIT codon D816 and PDGFRA codon 842. Notably our data indicate that sorafenib is more effective than imatinib or sunitinib for inhibiting the kinase activity of drug-resistant KIT mutants (as assessed by biochemical IC50). We hypothesize that a major determinant of the efficacy of sorafenib for treatment of advanced GIST is the activity of this agent against KIT or PDGFRA-mutant kinases. These results have implications for the further development of treatments for drug-resistant GIST.

    AB - Sorafenib has substantial clinical activity as third- or fourth-line treatment of imatinib- and sunitinib-resistant gastrointestinal stromal tumors (GIST). Because sorafenib targets both angiogenesis-related kinases (VEGFR) and the pathogenetic kinases found in GIST (KIT or PDGFRA), the molecular basis for sorafenib efficacy in this setting remains unknown. We sought to determine the spectrum of activity of sorafenib against different mutant kinases associated with drug-sensitive and drug-resistant GIST. We compared the activity of imatinib and sorafenib against transiently expressed mutant forms of KIT and PDGFRA, including various secondary mutations that have been identified in imatinib-resistant or sunitinib-resistant GISTs. We also examined these drugs against four GIST cell lines, three of which are imatinib resistant. In our in vitro studies, we determined that sorafenib inhibited imatinib-resistant mutations in exons encoding the ATP/drug-binding pocket and in exons encoding the activation loop, with the exception of substitutions at KIT codon D816 and PDGFRA codon 842. Notably our data indicate that sorafenib is more effective than imatinib or sunitinib for inhibiting the kinase activity of drug-resistant KIT mutants (as assessed by biochemical IC50). We hypothesize that a major determinant of the efficacy of sorafenib for treatment of advanced GIST is the activity of this agent against KIT or PDGFRA-mutant kinases. These results have implications for the further development of treatments for drug-resistant GIST.

    UR - http://www.scopus.com/inward/record.url?scp=84864874062&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84864874062&partnerID=8YFLogxK

    U2 - 10.1158/1535-7163.MCT-12-0223

    DO - 10.1158/1535-7163.MCT-12-0223

    M3 - Article

    C2 - 22665524

    AN - SCOPUS:84864874062

    VL - 11

    SP - 1770

    EP - 1780

    JO - Molecular Cancer Therapeutics

    JF - Molecular Cancer Therapeutics

    SN - 1535-7163

    IS - 8

    ER -