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.

2.50
Hdl Handle:
http://hdl.handle.net/10541/109349
Title:
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.
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
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.
Affiliation:
AstraZeneca, Macclesfield, United Kingdom; AstraZeneca, Reims, France.
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
Issue Date:
15-Feb-2010
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
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
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.en
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

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