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    AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor, ERBB2 (HER2), and ERBB3: a unique agent for simultaneous ERBB receptor blockade in cancer.

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    Authors
    Hickinson, D Mark
    Klinowska, Teresa
    Speake, Georgina
    Vincent, John
    Trigwell, Cath
    Anderton, Judith
    Beck, Sarah
    Marshall, Gayle
    Davenport, Sara
    Callis, Rowena
    Mills, Elizabeth
    Grosios, Konstantina
    Smith, Paul
    Barlaam, Bernard
    Wilkinson, Robert W
    Ogilvie, Donald J
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    Affiliation
    AstraZeneca, Macclesfield, United Kingdom; AstraZeneca, Reims, France.
    Issue Date
    2010-02-15
    
    Metadata
    Show full item record
    Abstract
    PURPOSE: To test the hypothesis that simultaneous, equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo. EXPERIMENTAL DESIGN: A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors. RESULTS: In vitro, AZD8931 showed equipotent, reversible inhibition of EGFR (IC(50), 4 nmol/L), erbB2 (IC(50), 3 nmol/L), and erbB3 (IC(50), 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non-small cell lung carcinoma cell lines. In vivo, AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. CONCLUSIONS: AZD8931 has a unique pharmacologic profile providing equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2.
    Citation
    AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor, ERBB2 (HER2), and ERBB3: a unique agent for simultaneous ERBB receptor blockade in cancer. 2010, 16 (4):1159-69 Clin. Cancer Res.
    Journal
    Clinical Cancer Research
    URI
    http://hdl.handle.net/10541/109349
    DOI
    10.1158/1078-0432.CCR-09-2353
    PubMed ID
    20145185
    Type
    Article
    Language
    en
    ISSN
    1078-0432
    ae974a485f413a2113503eed53cd6c53
    10.1158/1078-0432.CCR-09-2353
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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