Skip to main content
main-content

01.12.2014 | Research | Ausgabe 1/2014 Open Access

Journal of Experimental & Clinical Cancer Research 1/2014

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

Zeitschrift:
Journal of Experimental & Clinical Cancer Research > Ausgabe 1/2014
Autoren:
Zhaomei Mu, Teresa Klinowska, Xiaoshen Dong, Emily Foster, Chris Womack, Sandra V Fernandez, Massimo Cristofanilli
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1756-9966-33-47) contains supplementary material, which is available to authorized users.

Competing interests

Teresa Klinowska, Emily Foster and Chris Womack are employees of and stockholders in AstraZeneca. All other authors declare that they have no competing interests.

Authors’ contributions

ZM performed the experiments, analyzed the data and wrote the manuscript. TK, EF and CW assisted with immunohistochemical staining, analysed the data, reviewed and finalized the manuscript. XD and SF assisted with in vivo experiments. MC conceived of the study and finalized the manuscript. All authors read and approved the final manuscript.

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.
Zusatzmaterial
Authors’ original file for figure 1
13046_2014_777_MOESM1_ESM.pdf
Authors’ original file for figure 2
13046_2014_777_MOESM2_ESM.pdf
Authors’ original file for figure 3
13046_2014_777_MOESM3_ESM.pdf
Authors’ original file for figure 4
13046_2014_777_MOESM4_ESM.pdf
Authors’ original file for figure 5
13046_2014_777_MOESM5_ESM.jpeg
Literatur
Über diesen Artikel

Weitere Artikel der Ausgabe 1/2014

Journal of Experimental & Clinical Cancer Research 1/2014 Zur Ausgabe

Neu im Fachgebiet Onkologie

Mail Icon II Newsletter

Bestellen Sie unseren kostenlosen Newsletter Update Onkologie und bleiben Sie gut informiert – ganz bequem per eMail.

Bildnachweise