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Targeting trastuzumab-resistant breast cancer cells with a lentivirus engineered to bind antibodies that recognize HER-2

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Abstract

Targeting HER-2 over-expressing breast cancer cells with trastuzumab has resulted in significant improvements in both disease-free and overall survival rates. However, despite a favorable initial response, some cancer cells become resistant and develop into fatal metastatic disease. Here we report that we can specifically target HER-2 over-expressing and trastuzumab-resistant breast cancer cells by using an engineered lentivirus which has trastuzumab bound to its envelope. In vitro, this lentiviral construct mediated both the expression of reporter genes, such as enhanced green fluorescent protein (EGFP) and firefly luciferase, as well as the therapeutic gene, herpes thymidine kinase (hTK), in HER-2 over-expressing cells. Subsequent application of the pro-drug ganciclovir selectively killed breast cancer cells in which lentivirus mediated expression of hTK. In vivo, we successfully targeted the expression of firefly luciferase to trastuzumab-resistant breast cancer tumors established in nude mice. Furthermore, we found that systemic administration of trastuzumab-bound lentivirus led to expression of EGFP in circulating trastuzumab-resistant breast cancer cells. In conclusion, HER-2 over-expressing breast cancer cells resistant to trastuzumab can be targeted for selective gene expression and destruction by viruses with envelope-proteins engineered to bind to this antibody.

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Acknowledgments

This work was supported by a grant from the Terry Fox Foundation. The authors also thank Rowena Lee of the BC Cancer Agency for providing the trastuzumab, Dr. Dieter Fink for providing vectors expressing EGFP and Bsr, as well as Dr Robert Snoek, Jessica Firus, and Brenda Prieur for their critical reading of the manuscript.

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Authors and Affiliations

  1. The Vancouver Prostate Centre, 2660 Oak Street, Vancouver, BC, V6H-3Z6, Canada

    Kai-xin Zhang, Connie Kim, Elaine Chow & Paul S. Rennie

  2. David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Irvin S. Y. Chen

  3. Department of Surgery and Brain Research Centre, University of British Columbia, Vancouver, BC, Canada

    William Jia

  4. Department of Urological Sciences, University of British Columbia, Vancouver, BC, Canada

    Paul S. Rennie

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  1. Kai-xin Zhang
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  2. Connie Kim
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  3. Elaine Chow
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  4. Irvin S. Y. Chen
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  5. William Jia
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  6. Paul S. Rennie
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Correspondence to Paul S. Rennie.

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Zhang, Kx., Kim, C., Chow, E. et al. Targeting trastuzumab-resistant breast cancer cells with a lentivirus engineered to bind antibodies that recognize HER-2. Breast Cancer Res Treat 125, 89–97 (2011). https://doi.org/10.1007/s10549-010-0828-9

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  • DOI: https://doi.org/10.1007/s10549-010-0828-9

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