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dc.contributor.authorHickinson, D Marken
dc.contributor.authorKlinowska, Teresaen
dc.contributor.authorSpeake, Georginaen
dc.contributor.authorVincent, Johnen
dc.contributor.authorTrigwell, Cathen
dc.contributor.authorAnderton, Judithen
dc.contributor.authorBeck, Sarahen
dc.contributor.authorMarshall, Gayleen
dc.contributor.authorDavenport, Saraen
dc.contributor.authorCallis, Rowenaen
dc.contributor.authorMills, Elizabethen
dc.contributor.authorGrosios, Konstantinaen
dc.contributor.authorSmith, Paulen
dc.contributor.authorBarlaam, Bernarden
dc.contributor.authorWilkinson, Robert Wen
dc.contributor.authorOgilvie, Donald Jen
dc.date.accessioned2010-08-09T16:29:01Z
dc.date.available2010-08-09T16:29:01Z
dc.date.issued2010-02-15
dc.identifier.citationAZD8931, 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.en
dc.identifier.issn1078-0432
dc.identifier.pmid20145185
dc.identifier.doi10.1158/1078-0432.CCR-09-2353
dc.identifier.urihttp://hdl.handle.net/10541/109349
dc.description.abstractPURPOSE: 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.
dc.language.isoenen
dc.subjectTumour Cell Lineen
dc.subjectHead and Neck Canceren
dc.subjectXenograft Model Antitumour Assaysen
dc.subject.meshAnimals
dc.subject.meshCarcinoma, Squamous Cell
dc.subject.meshCell Line, Tumor
dc.subject.meshCell Proliferation
dc.subject.meshHead and Neck Neoplasms
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshMice, Nude
dc.subject.meshMice, SCID
dc.subject.meshQuinazolines
dc.subject.meshReceptor, Epidermal Growth Factor
dc.subject.meshReceptor, erbB-2
dc.subject.meshReceptor, erbB-3
dc.subject.meshSignal Transduction
dc.subject.meshXenograft Model Antitumor Assays
dc.titleAZD8931, 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.en
dc.typeArticleen
dc.contributor.departmentAstraZeneca, Macclesfield, United Kingdom; AstraZeneca, Reims, France.en
dc.identifier.journalClinical Cancer Researchen
html.description.abstractPURPOSE: 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.


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