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

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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.

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  1. Carmel T. Chan

    Present address: Department of Radiology, Stanford University School of Medicine, James Clark Center E150, Stanford, CA, USA

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  1. Division of Molecular Medicine, Beckman Research Institute of the City of Hope, 1500 E. Duarte Road, Duarte, CA, 91010, USA

    Carmel T. Chan, Marianne Z. Metz & Susan E. Kane

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Chan, C.T., Metz, M.Z. & Kane, S.E. Differential sensitivities of trastuzumab (Herceptin®)-resistant human breast cancer cells to phosphoinositide-3 kinase (PI-3K) and epidermal growth factor receptor (EGFR) kinase inhibitors. Breast Cancer Res Treat 91, 187–201 (2005). https://doi.org/10.1007/s10549-004-7715-1

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