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AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), HER2, and HER3: preclinical activity in HER2 non-amplified inflammatory breast cancer models.

Mu Z, Klinowska T, Dong X, Foster E, Womack C, Fernandez SV, Cristofanilli M - J. Exp. Clin. Cancer Res. (2014)

Bottom Line: Epidermal growth factor receptor (EGFR) overexpression has been associated with prognostic and predictive value in inflammatory breast cancer (IBC).AZD8931 significantly suppressed cell growth of IBC cells and induced apoptosis of human IBC cells in vitro.Significantly, we showed that AZD8931 monotherapy inhibited xenograft growth and the combination of paclitaxel + AZD8931 was demonstrably more effective than paclitaxel or AZD8931 alone treatment at delaying tumor growth in vivo in orthotopic IBC models.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Oncology, Thomas Jefferson University; and Kimmel Cancer Center, Philadelphia, PA 19107, USA. Zhaomei.Mu@jefferson.edu.

ABSTRACT

Introduction: Epidermal growth factor receptor (EGFR) overexpression has been associated with prognostic and predictive value in inflammatory breast cancer (IBC). Epidermal growth factor receptor 2 (HER2) overexpression is observed at a higher rate in IBC compared with noninflammatory breast cancer. Current clinically available anti-HER2 therapies are effective only in patients with HER2 amplified breast cancer, including IBC. AZD8931 is a novel small-molecule equipotent inhibitor of EGFR, HER2, and HER3 signaling. In this study, we investigated the antitumor activity of AZD8931 alone or in combination with paclitaxel using preclinical models of EGFR-overexpressed and HER2 non-amplified IBC cells.

Methods: Two IBC cell lines SUM149 and FC-IBC-02 derived from pleural effusion of an IBC patient were used in this study. Cell growth and apoptotic cell death were examined in vitro. For the in vivo tumor growth studies, IBC cells were orthotopically transplanted into the mammary fat pads of immunodeficient mice. AZD8931 was given by daily oral gavage at doses of 25 mg/kg, 5 days/week for 4 weeks. Paclitaxel was subcutaneously injected twice weekly.

Results: AZD8931 significantly suppressed cell growth of IBC cells and induced apoptosis of human IBC cells in vitro. Significantly, we showed that AZD8931 monotherapy inhibited xenograft growth and the combination of paclitaxel + AZD8931 was demonstrably more effective than paclitaxel or AZD8931 alone treatment at delaying tumor growth in vivo in orthotopic IBC models.

Conclusion: AZD8931 single agent and in combination with paclitaxel demonstrated signal inhibition and antitumor activity in EGFR-overexpressed and HER2 non-amplified IBC models. These results suggest that AZD8931 may provide a novel therapeutic strategy for the treatment of IBC patients with HER2 non-amplified tumors.

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Related in: MedlinePlus

AZD8931 inhibits EGFR pathway protein expression. A. SUM149 cells were treated with vehicle control or 1 μmol/L AZD8931 for 4, 24, and 48 hrs. B. SUM149 and FC-IBC-02 cells were treated with 0 (vehicle), 0.01, 0.1, or 1 μmol/L AZD8931 for 24 hrs. Expression of EGFR, p-Akt, Akt, and β-Actin was examined by immunoblot analysis.
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Figure 2: AZD8931 inhibits EGFR pathway protein expression. A. SUM149 cells were treated with vehicle control or 1 μmol/L AZD8931 for 4, 24, and 48 hrs. B. SUM149 and FC-IBC-02 cells were treated with 0 (vehicle), 0.01, 0.1, or 1 μmol/L AZD8931 for 24 hrs. Expression of EGFR, p-Akt, Akt, and β-Actin was examined by immunoblot analysis.

Mentions: Previous study showed that AZD8931 is an equipotent, reversible inhibitor of EGFR, HER2 and HER3 signaling with potent in vitro inhibition of EGFR, HER2 and HER3 phosphorylation in breast cancer and squamous carcinoma cells[16]. As SUM149 and FC-IBC-02 cells express a high level of EGFR and low levels of HER2 and HER3, we sought to determine the effects of AZD8931 on the protein expression of EGFR and downstream markers. We tested the effects of AZD8931 on EGFR, phospho-Akt. in SUM149 cells at different time points. Western blot analysis showed that AZD8931 had no significant effect on EGFR expression level, and significantly inhibited phosphorylation of Akt in a time-dependent manner (Figure 2A). The inhibition of phospho-Akt was dose-dependent in both SUM149 and FC-IBC-02 cells (Figure 2B).


AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), HER2, and HER3: preclinical activity in HER2 non-amplified inflammatory breast cancer models.

Mu Z, Klinowska T, Dong X, Foster E, Womack C, Fernandez SV, Cristofanilli M - J. Exp. Clin. Cancer Res. (2014)

AZD8931 inhibits EGFR pathway protein expression. A. SUM149 cells were treated with vehicle control or 1 μmol/L AZD8931 for 4, 24, and 48 hrs. B. SUM149 and FC-IBC-02 cells were treated with 0 (vehicle), 0.01, 0.1, or 1 μmol/L AZD8931 for 24 hrs. Expression of EGFR, p-Akt, Akt, and β-Actin was examined by immunoblot analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4061513&req=5

Figure 2: AZD8931 inhibits EGFR pathway protein expression. A. SUM149 cells were treated with vehicle control or 1 μmol/L AZD8931 for 4, 24, and 48 hrs. B. SUM149 and FC-IBC-02 cells were treated with 0 (vehicle), 0.01, 0.1, or 1 μmol/L AZD8931 for 24 hrs. Expression of EGFR, p-Akt, Akt, and β-Actin was examined by immunoblot analysis.
Mentions: Previous study showed that AZD8931 is an equipotent, reversible inhibitor of EGFR, HER2 and HER3 signaling with potent in vitro inhibition of EGFR, HER2 and HER3 phosphorylation in breast cancer and squamous carcinoma cells[16]. As SUM149 and FC-IBC-02 cells express a high level of EGFR and low levels of HER2 and HER3, we sought to determine the effects of AZD8931 on the protein expression of EGFR and downstream markers. We tested the effects of AZD8931 on EGFR, phospho-Akt. in SUM149 cells at different time points. Western blot analysis showed that AZD8931 had no significant effect on EGFR expression level, and significantly inhibited phosphorylation of Akt in a time-dependent manner (Figure 2A). The inhibition of phospho-Akt was dose-dependent in both SUM149 and FC-IBC-02 cells (Figure 2B).

Bottom Line: Epidermal growth factor receptor (EGFR) overexpression has been associated with prognostic and predictive value in inflammatory breast cancer (IBC).AZD8931 significantly suppressed cell growth of IBC cells and induced apoptosis of human IBC cells in vitro.Significantly, we showed that AZD8931 monotherapy inhibited xenograft growth and the combination of paclitaxel + AZD8931 was demonstrably more effective than paclitaxel or AZD8931 alone treatment at delaying tumor growth in vivo in orthotopic IBC models.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Oncology, Thomas Jefferson University; and Kimmel Cancer Center, Philadelphia, PA 19107, USA. Zhaomei.Mu@jefferson.edu.

ABSTRACT

Introduction: Epidermal growth factor receptor (EGFR) overexpression has been associated with prognostic and predictive value in inflammatory breast cancer (IBC). Epidermal growth factor receptor 2 (HER2) overexpression is observed at a higher rate in IBC compared with noninflammatory breast cancer. Current clinically available anti-HER2 therapies are effective only in patients with HER2 amplified breast cancer, including IBC. AZD8931 is a novel small-molecule equipotent inhibitor of EGFR, HER2, and HER3 signaling. In this study, we investigated the antitumor activity of AZD8931 alone or in combination with paclitaxel using preclinical models of EGFR-overexpressed and HER2 non-amplified IBC cells.

Methods: Two IBC cell lines SUM149 and FC-IBC-02 derived from pleural effusion of an IBC patient were used in this study. Cell growth and apoptotic cell death were examined in vitro. For the in vivo tumor growth studies, IBC cells were orthotopically transplanted into the mammary fat pads of immunodeficient mice. AZD8931 was given by daily oral gavage at doses of 25 mg/kg, 5 days/week for 4 weeks. Paclitaxel was subcutaneously injected twice weekly.

Results: AZD8931 significantly suppressed cell growth of IBC cells and induced apoptosis of human IBC cells in vitro. Significantly, we showed that AZD8931 monotherapy inhibited xenograft growth and the combination of paclitaxel + AZD8931 was demonstrably more effective than paclitaxel or AZD8931 alone treatment at delaying tumor growth in vivo in orthotopic IBC models.

Conclusion: AZD8931 single agent and in combination with paclitaxel demonstrated signal inhibition and antitumor activity in EGFR-overexpressed and HER2 non-amplified IBC models. These results suggest that AZD8931 may provide a novel therapeutic strategy for the treatment of IBC patients with HER2 non-amplified tumors.

Show MeSH
Related in: MedlinePlus