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

S. Chandarlapaty, M. Scaltriti, P. Angelini, Q. Ye, M. Guzman, C. A. Hudis, L. Norton, D. B. Solit, J. Arribas, J. Baselga, N. Rosen

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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. © 2010 Macmillan Publishers Limited All rights reserved.
Original languageEnglish
Pages (from-to)325-334
JournalOncogene
Volume29
Issue number3
DOIs
Publication statusPublished - 1 Jan 2010

Keywords

  • Breast cancer
  • HER2
  • P95-HER2
  • Trastuzumab

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    Chandarlapaty, S., Scaltriti, M., Angelini, P., Ye, Q., Guzman, M., Hudis, C. A., Norton, L., Solit, D. B., Arribas, J., Baselga, J., & Rosen, N. (2010). Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growth. Oncogene, 29(3), 325-334. https://doi.org/10.1038/onc.2009.337