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Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growth

Abstract

The anti-HER2 antibody Trastuzumab (Herceptin) has been proven to be effective in the treatment of HER2-overexpressing breast cancer; resistance, however, invariably emerges in metastatic tumors. The expression of p95-HER2, a form of HER2 with a truncated extracellular domain that lacks the Trastuzumab binding epitope, has been implicated as a mechanism of resistance to the antibody. We utilized an in vivo tumor model that overexpresses p95-HER2 and showed it to be resistant to the signaling and antitumor effects of Trastuzumab. We find that both full-length and p95-HER2 interact with the HSP90 chaperone protein and are degraded in tumor cells exposed to HSP90 inhibitors in tissue culture and in vivo. Loss of expression of p95-HER2 is accompanied by downregulation of the phosphoinositide-3 kinase/AKT and extracellular signal-regulated kinase signaling pathways and inhibition of cell proliferation. Chronic administration of HSP90 inhibitors in vivo results in sustained loss of HER2 and p95-HER2 expression and inhibition of AKT activation, together with induction of apoptosis and complete inhibition of tumor growth in Trastuzumab-resistant, p95-HER2-overexpressing models. Thus, p95-HER2 is an HSP90 client protein, the expression and function of which can be effectively suppressed in vivo by HSP90 inhibitors. HSP90 inhibition is therefore a potentially effective therapeutic strategy for p95-HER2-mediated Trastuzumab-resistant breast cancer.

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Acknowledgements

We thank Gail Lewis Phillips and Mark Sliwkowski for providing the Fo5 tumors for this study. We also thank Elisa DeStanchina and Wai Wong for their assistance with animal studies. This work is supported by the National Institute of Health Program Grant P01-CA094060, the Breast Cancer Research Foundation and the generous support of Arlene Taub. S Chandarlapaty is supported by an ASCO Foundation Young Investigator Award.

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Correspondence to N Rosen.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Chandarlapaty, S., Scaltriti, M., Angelini, P. et al. Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growth. Oncogene 29, 325–334 (2010). https://doi.org/10.1038/onc.2009.337

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