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Breast Cancer Research and Treatment

, Volume 129, Issue 2, pp 387–400 | Cite as

The PI3 kinase/mTOR blocker NVP-BEZ235 overrides resistance against irreversible ErbB inhibitors in breast cancer cells

  • Caroline Brünner-Kubath
  • Waheed Shabbir
  • Victoria Saferding
  • Renate Wagner
  • Christian F. Singer
  • Peter Valent
  • Walter Berger
  • Brigitte Marian
  • Christoph C. Zielinski
  • Michael Grusch
  • Thomas W. Grunt
Preclinical study

Abstract

Resistance against first and second generation (irreversible) ErbB inhibitors is an unsolved problem in clinical oncology. The purpose of this study was to examine the effects of the irreversible ErbB inhibitors pelitinib and canertinib on growth of breast and ovarian cancer cells. Although in vitro growth-inhibitory effects of both drugs exceeded by far the effects of all reversible ErbB blockers tested (lapatinib, erlotinib, and gefitinib), complete growth inhibition was usually not reached. To define the mechanism of resistance, we examined downstream signaling pathways in drug-exposed cells by Western blot analysis. Although ErbB phosphorylation was reduced by pelitinib and canertinib, activation of the AKT/mTOR pathway remained essentially unaltered in drug-resistant cells. Correspondingly, transfection of tumor cells with constitutively activated AKT was found to promote resistance against all ErbB inhibitors tested, whereas dominant negative AKT reinstalled sensitivity in drug-resistant cells. In a next step, we applied PI3K/AKT/mTOR blockers including the dual PI3K/mTOR kinase inhibitor NVP-BEZ235. These agents were found to cooperate with pelitinib and canertinib in producing in vitro growth inhibition in cancer cells resistant against ErbB-targeting drugs. In conclusion, our data show that ErbB drug-refractory activation of the PI3K/AKT/mTOR pathway plays a crucial role in resistance against classical and second-generation irreversible ErbB inhibitors, and NVP-BEZ235 can override this form of resistance against pelitinib and canertinib.

Keywords

Breast cancer Drug resistance Irreversible EGFR/ErbB/HER inhibitor Ovarian cancer NVP-BEZ235 PI3K/AKT/mTOR 

Notes

Acknowledgments

Pelitinib (EKB-569) and canertinib (CI-1033) were kindly provided by Wyeth and Pfizer, respectively. A2774, A2780, A2780ADR, H134, HEY, HOC-7, TR170, and CEM cells were generous gifts from M. Krainer (Medical Univ. Vienna, Austria), H.J. Broxterman (Free Univ. Hospital, Amsterdam, The Netherlands), R. N. Buick (Univ. Toronto, ON, Canada), B.T. Hill (Imperial Cancer Research Fund, London, UK), and U. Jaeger (Medical Univ. Vienna, Austria), respectively. Human myc-HA-MEK1/pBluescript KS was kindly obtained from H. Kiyama (Osaka City Univ., Osaka, Japan), murine dominant active AKT1 was generously provided by D. Efremov (International Center for Genetic Engineering and Biotechnology, Rome, Italy), and human dominant negative AKT was a kind gift from M. Sibilia (Medical Univ. Vienna, Austria). This work was supported by the “Medical Scientific Fund of the Mayor of the City of Vienna” (#08037) and by the “Initiative Krebsforschung” of the Medical University Vienna.

Supplementary material

10549_2010_1232_MOESM1_ESM.doc (2.1 mb)
Supplementary material 1 (DOC 2147 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Caroline Brünner-Kubath
    • 1
  • Waheed Shabbir
    • 1
  • Victoria Saferding
    • 1
  • Renate Wagner
    • 1
  • Christian F. Singer
    • 2
  • Peter Valent
    • 3
    • 6
  • Walter Berger
    • 4
  • Brigitte Marian
    • 4
  • Christoph C. Zielinski
    • 5
    • 6
  • Michael Grusch
    • 4
  • Thomas W. Grunt
    • 1
    • 5
    • 6
  1. 1.Signaling Networks Program, Division of Oncology, Department of Medicine IMedical University ViennaViennaAustria
  2. 2.Department of Obstetrics/GynecologyMedical University ViennaViennaAustria
  3. 3.Division of Hematology/HemostaseologyMedical University ViennaViennaAustria
  4. 4.Institute of Cancer Research, Department of Medicine IMedical University ViennaViennaAustria
  5. 5.Division of Oncology, Department of Medicine IMedical University ViennaViennaAustria
  6. 6.Ludwig Boltzmann Cluster OncologyViennaAustria

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