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Breast Cancer Research and Treatment

, Volume 144, Issue 2, pp 263–272 | Cite as

Therapeutic potential of the dual EGFR/HER2 inhibitor AZD8931 in circumventing endocrine resistance

  • Gladys Morrison
  • Xiaoyong Fu
  • Martin Shea
  • Sarmistha Nanda
  • Mario Giuliano
  • Tao Wang
  • Teresa Klinowska
  • C. Kent Osborne
  • Mothaffar F. Rimawi
  • Rachel Schiff
Preclinical Study

Abstract

Modest up-regulation of either HER-ligands or receptors has been implicated in acquired endocrine resistance. AZD8931, a dual tyrosine kinase inhibitor (TKI) of epithelial growth factor receptor (EGFR)/HER2, has been shown to more effectively block ligand-dependent HER signaling than the HER TKIs lapatinib or gefitinib. We therefore examined the effect of AZD8931 in ER-positive/HER2-negative breast cancer cells with acquired resistance to tamoxifen, where there is ligand up-regulation associated with HER pathway activation. RNA-seq ligand profiling and levels of HER receptors and signaling by western blotting were conducted in ER+ MCF7 and T47D parental cells and their Tam-resistant derivatives (TamRes). In vitro cell growth and apoptosis and HER ligand-stimulated signaling were measured in response to endocrine and HER TKIs. For studies in vivo, transplantable MCF7/TamRes xenografts were treated with tamoxifen or fulvestrant, either alone or in combination with AZD8931. AZD8931 only minimally enhanced endocrine sensitivity in MCF7 parental cells, but showed a greater effect in the T47D parental model. AZD8931 combined with either tamoxifen or fulvestrant inhibited cell growth more than lapatinib in T47D TamRes cells, and was also significantly, though modestly, more potent in MCF7 TamRes cells. In both TamRes models, AZD8931 significantly inhibited cell proliferation and induced apoptosis. Under ligand-stimulated conditions, AZD8931 more potently inhibited HER signaling than lapatinib or gefitinib. AZD8931 also significantly delayed the growth of MCF7 TamRes xenografts in the presence of tamoxifen or fulvestrant. The strongest inhibition was achieved with a fulvestrant and AZD8931 combination, though no tumor regression was observed. This study provides evidence that AZD8931 has greater inhibitory efficacy in tamoxifen-resistant settings than in an endocrine therapy naïve setting. The absence of tumor regression, however, suggests that additional escape pathways contribute to resistant growth and will need to be targeted to fully circumvent tamoxifen resistance.

Keywords

Estrogen receptor Growth factor receptors Endocrine therapy Endocrine resistance AZD8931 HER-ligands Combination therapy 

Notes

Acknowledgments

We thank T. Mitchell for assistance with the mouse studies and Dr. G. Chamness for discussing and reviewing this manuscript. This work was supported in part by the Dan L. Duncan Cancer Center Grant P30CA125123, the Breast Cancer Research Foundation (R. Schiff and C.K. Osborne), the AstraZeneca Research Grant, and Susan G. Komen for the Cure Foundation Promise Grant PG12221410.

Conflict of interest

R. Schiff, M. Rimawi, and C.K. Osborne have received research funding from AstraZeneca. T. Klinowska is an employee of AstraZeneca.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Gladys Morrison
    • 1
    • 2
  • Xiaoyong Fu
    • 1
  • Martin Shea
    • 1
  • Sarmistha Nanda
    • 1
  • Mario Giuliano
    • 1
  • Tao Wang
    • 1
  • Teresa Klinowska
    • 4
  • C. Kent Osborne
    • 1
    • 2
    • 3
  • Mothaffar F. Rimawi
    • 1
    • 2
    • 3
  • Rachel Schiff
    • 1
    • 2
    • 3
  1. 1.Lester and Sue Smith Breast Center and Dan L Duncan Cancer CenterBaylor College of MedicineHoustonUSA
  2. 2.Translational Biology and Molecular MedicineBaylor College of MedicineHoustonUSA
  3. 3.Department of MedicineBaylor College of MedicineHoustonUSA
  4. 4.AstraZeneca Oncology iMedMacclesfieldUK

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