Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors

Michael Heinrich, Diana Griffith, Arin McKinley, Janice Patterson, Ajia Presnell, Abhijit Ramachandran, Maria Debiec-Rychter

    Research output: Contribution to journalArticle

    121 Citations (Scopus)

    Abstract

    Purpose: To determine the potential of crenolanib, a potent inhibitor of PDGFRA, to treat malignancies driven by mutant PDGFRA. Experimental Design: The biochemical activity of crenolanib was compared with imatinib using a panel of PDGFRA-mutant kinases expressed in several different cell line models, including primary gastrointestinal stromal tumors (GIST) cells. The antiproliferative activity of crenolanib was also studied in several cell lines with PDGFRA-dependent growth. Results: Crenolanib was significantly more potent than imatinib in inhibiting the kinase activity of imatinib-resistant PDGFRA kinases (D842I, D842V, D842Y, DI842-843IM, and deletion I843). For example, crenolanib was 135-fold more potent than imatinib against D842V in our isogenic model system, with an IC50 of approximately 10 nmol/L. The relative potency of crenolanib was further confirmed in BaF3 and primary GIST cells expressing PDGFRA D842V. In contrast, imatinib was at least 10-fold more potent than crenolanib in inhibiting the V561D mutation. For all other tested PDGFRA mutations, crenolanib and imatinib had comparable potency. Conclusions: Crenolanib is a potent inhibitor of imatinib-resistant PDGFRA kinases associated with GIST, including the PDGFRA D842V mutation found in approximately 5% of GISTs. The spectrum of activity of crenolanib suggests that this drug is a type I inhibitor (inhibitor of activated conformation of kinase). Based in part on these results, a phase II clinical study of this agent to treat GIST with the PDGFRA D842V mutation has been initiated.

    Original languageEnglish (US)
    Pages (from-to)4375-4384
    Number of pages10
    JournalClinical Cancer Research
    Volume18
    Issue number16
    DOIs
    StatePublished - Aug 15 2012

    Fingerprint

    Gastrointestinal Stromal Tumors
    Mutation
    Pharmaceutical Preparations
    Phosphotransferases
    Stromal Cells
    Imatinib Mesylate
    crenolanib
    Cell Line
    Inhibitory Concentration 50
    Research Design

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors. / Heinrich, Michael; Griffith, Diana; McKinley, Arin; Patterson, Janice; Presnell, Ajia; Ramachandran, Abhijit; Debiec-Rychter, Maria.

    In: Clinical Cancer Research, Vol. 18, No. 16, 15.08.2012, p. 4375-4384.

    Research output: Contribution to journalArticle

    Heinrich, Michael ; Griffith, Diana ; McKinley, Arin ; Patterson, Janice ; Presnell, Ajia ; Ramachandran, Abhijit ; Debiec-Rychter, Maria. / Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 16. pp. 4375-4384.
    @article{783dfb60386d43f8a5398e36c5e7d89c,
    title = "Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors",
    abstract = "Purpose: To determine the potential of crenolanib, a potent inhibitor of PDGFRA, to treat malignancies driven by mutant PDGFRA. Experimental Design: The biochemical activity of crenolanib was compared with imatinib using a panel of PDGFRA-mutant kinases expressed in several different cell line models, including primary gastrointestinal stromal tumors (GIST) cells. The antiproliferative activity of crenolanib was also studied in several cell lines with PDGFRA-dependent growth. Results: Crenolanib was significantly more potent than imatinib in inhibiting the kinase activity of imatinib-resistant PDGFRA kinases (D842I, D842V, D842Y, DI842-843IM, and deletion I843). For example, crenolanib was 135-fold more potent than imatinib against D842V in our isogenic model system, with an IC50 of approximately 10 nmol/L. The relative potency of crenolanib was further confirmed in BaF3 and primary GIST cells expressing PDGFRA D842V. In contrast, imatinib was at least 10-fold more potent than crenolanib in inhibiting the V561D mutation. For all other tested PDGFRA mutations, crenolanib and imatinib had comparable potency. Conclusions: Crenolanib is a potent inhibitor of imatinib-resistant PDGFRA kinases associated with GIST, including the PDGFRA D842V mutation found in approximately 5{\%} of GISTs. The spectrum of activity of crenolanib suggests that this drug is a type I inhibitor (inhibitor of activated conformation of kinase). Based in part on these results, a phase II clinical study of this agent to treat GIST with the PDGFRA D842V mutation has been initiated.",
    author = "Michael Heinrich and Diana Griffith and Arin McKinley and Janice Patterson and Ajia Presnell and Abhijit Ramachandran and Maria Debiec-Rychter",
    year = "2012",
    month = "8",
    day = "15",
    doi = "10.1158/1078-0432.CCR-12-0625",
    language = "English (US)",
    volume = "18",
    pages = "4375--4384",
    journal = "Clinical Cancer Research",
    issn = "1078-0432",
    publisher = "American Association for Cancer Research Inc.",
    number = "16",

    }

    TY - JOUR

    T1 - Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors

    AU - Heinrich, Michael

    AU - Griffith, Diana

    AU - McKinley, Arin

    AU - Patterson, Janice

    AU - Presnell, Ajia

    AU - Ramachandran, Abhijit

    AU - Debiec-Rychter, Maria

    PY - 2012/8/15

    Y1 - 2012/8/15

    N2 - Purpose: To determine the potential of crenolanib, a potent inhibitor of PDGFRA, to treat malignancies driven by mutant PDGFRA. Experimental Design: The biochemical activity of crenolanib was compared with imatinib using a panel of PDGFRA-mutant kinases expressed in several different cell line models, including primary gastrointestinal stromal tumors (GIST) cells. The antiproliferative activity of crenolanib was also studied in several cell lines with PDGFRA-dependent growth. Results: Crenolanib was significantly more potent than imatinib in inhibiting the kinase activity of imatinib-resistant PDGFRA kinases (D842I, D842V, D842Y, DI842-843IM, and deletion I843). For example, crenolanib was 135-fold more potent than imatinib against D842V in our isogenic model system, with an IC50 of approximately 10 nmol/L. The relative potency of crenolanib was further confirmed in BaF3 and primary GIST cells expressing PDGFRA D842V. In contrast, imatinib was at least 10-fold more potent than crenolanib in inhibiting the V561D mutation. For all other tested PDGFRA mutations, crenolanib and imatinib had comparable potency. Conclusions: Crenolanib is a potent inhibitor of imatinib-resistant PDGFRA kinases associated with GIST, including the PDGFRA D842V mutation found in approximately 5% of GISTs. The spectrum of activity of crenolanib suggests that this drug is a type I inhibitor (inhibitor of activated conformation of kinase). Based in part on these results, a phase II clinical study of this agent to treat GIST with the PDGFRA D842V mutation has been initiated.

    AB - Purpose: To determine the potential of crenolanib, a potent inhibitor of PDGFRA, to treat malignancies driven by mutant PDGFRA. Experimental Design: The biochemical activity of crenolanib was compared with imatinib using a panel of PDGFRA-mutant kinases expressed in several different cell line models, including primary gastrointestinal stromal tumors (GIST) cells. The antiproliferative activity of crenolanib was also studied in several cell lines with PDGFRA-dependent growth. Results: Crenolanib was significantly more potent than imatinib in inhibiting the kinase activity of imatinib-resistant PDGFRA kinases (D842I, D842V, D842Y, DI842-843IM, and deletion I843). For example, crenolanib was 135-fold more potent than imatinib against D842V in our isogenic model system, with an IC50 of approximately 10 nmol/L. The relative potency of crenolanib was further confirmed in BaF3 and primary GIST cells expressing PDGFRA D842V. In contrast, imatinib was at least 10-fold more potent than crenolanib in inhibiting the V561D mutation. For all other tested PDGFRA mutations, crenolanib and imatinib had comparable potency. Conclusions: Crenolanib is a potent inhibitor of imatinib-resistant PDGFRA kinases associated with GIST, including the PDGFRA D842V mutation found in approximately 5% of GISTs. The spectrum of activity of crenolanib suggests that this drug is a type I inhibitor (inhibitor of activated conformation of kinase). Based in part on these results, a phase II clinical study of this agent to treat GIST with the PDGFRA D842V mutation has been initiated.

    UR - http://www.scopus.com/inward/record.url?scp=84865074356&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84865074356&partnerID=8YFLogxK

    U2 - 10.1158/1078-0432.CCR-12-0625

    DO - 10.1158/1078-0432.CCR-12-0625

    M3 - Article

    C2 - 22745105

    AN - SCOPUS:84865074356

    VL - 18

    SP - 4375

    EP - 4384

    JO - Clinical Cancer Research

    JF - Clinical Cancer Research

    SN - 1078-0432

    IS - 16

    ER -