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.

Authors

Zhaomei Mu, Department of Medical Oncology, Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, PA 19107, United States ; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesFollow
Teresa Klinowska, AstraZeneca, Macclesfield, Cheshire, United Kingdom
Xiaoshen Dong, Department of Surgical Oncology, First Affiliated Hospital, China Medical University, Shenyang, China
Emily Foster, AstraZeneca, Macclesfield, Cheshire, United Kingdom
Chris Womack, AstraZeneca, Macclesfield, Cheshire, United Kingdom
Sandra V Fernandez, Department of Medical Oncology, Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, PA 19107, United States ; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesFollow
Massimo Cristofanilli, Department of Medical Oncology, Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, PA 19107, United States ; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesFollow

Document Type

Article

Publication Date

5-30-2014

Comments

This article has been peer reviewed. It was published in: Journal of Experimental and Clinical Cancer Research.

Volume 33, Issue 1, 30 May 2014, Article number 47.

The published version is available at DOI: 10.1186/1756-9966-33-47

Copyright © 2014 Mu et al.

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.

Recommended Citation

Mu, Zhaomei; Klinowska, Teresa; Dong, Xiaoshen; Foster, Emily; Womack, Chris; Fernandez, Sandra V; and Cristofanilli, Massimo, "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." (2014). Department of Medical Oncology Faculty Papers. Paper 33.
https://jdc.jefferson.edu/medoncfp/33

PubMed ID

24886365