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Breast Cancer Research and Treatment

, Volume 91, Issue 2, pp 187–201 | Cite as

Differential sensitivities of trastuzumab (Herceptin®)-resistant human breast cancer cells to phosphoinositide-3 kinase (PI-3K) and epidermal growth factor receptor (EGFR) kinase inhibitors

  • Carmel T. Chan
  • Marianne Z. Metz
  • Susan E. KaneEmail author
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Abstract

Her2 (erbB2/neu) is overexpressed in 25–30% of human breast cancers. Herceptin is a recombinant humanized Her2 antibody used to treat breast cancer patients with Her2 overexpression. Over a 5-month selection process, we isolated clones of BT474 (BT) human breast carcinoma cells (BT/HerR) that were resistant to Herceptin in vitro. In BT/HerR subclones, cell-surface, phosphorylated and total cellular Her2 protein remained high in the continuous presence of Herceptin. Likewise, the levels of cell-surface, phosphorylated, and total cellular Her3 and EGFR were either unchanged or only slightly elevated in BT/HerR subclones relative to BT cells. One BT/HerR subclone had substantially upregulated cell-surface EGFR, but this did not correlate with a higher relative resistance to Herceptin. In looking at the downstream PI-3K/Akt signaling pathway, phosphorylated and total Akt levels and Akt kinase activities were all sustained in BT/HerR subclones in the presence of Herceptin, but significantly downregulated in BT cells exposed to Herceptin. Whereas BT cells lost sensitivity to the PI-3K inhibitor LY294002 in the presence of Herceptin, BT/HerR subclones were equally sensitive to this agent in the presence and absence of Herceptin. This suggests that BT/HerR subclones acquired a Herceptin-resistant mechanism of PI-3K signaling. BT/HerR subclones were also sensitive to the EGFR kinase inhibitor AG1478 in the presence of Herceptin, to the same extent as BT cells. The BT/Her R subclones provide new insights into mechanisms of Herceptin resistance and suggest new treatment strategies in combination with other inhibitors targeted to signal transduction pathways.

Keywords

AG1478 Akt BT474 cells drug resistance epidermal growth factor receptor Her2 Herceptin LY294002 phosphatidylinositol-3 kinase 

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Copyright information

© Springer 2005

Authors and Affiliations

  • Carmel T. Chan
    • 1
    • 2
  • Marianne Z. Metz
    • 1
  • Susan E. Kane
    • 1
    Email author
  1. 1.Division of Molecular MedicineBeckman Research Institute of the City of HopeDuarteUSA
  2. 2.Department of RadiologyStanford University School of MedicineStanfordUSA

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