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

   


Authors: Chandarlapaty, S.; Scaltriti, M.; Angelini, P.; Ye, Q.; Guzman, M.; Hudis, C. A.; Norton, L.; Solit, D. B.; Arribas, J.; Baselga, J.; Rosen, N.
Article Title: 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. © 2010 Macmillan Publishers Limited All rights reserved.
Keywords: signal transduction; mitogen activated protein kinase; protein kinase b; controlled study; protein expression; unclassified drug; mutation; nonhuman; antineoplastic agents; neoplasms; cell proliferation; mouse; animals; mice; apoptosis; breast cancer; tumor volume; protein degradation; protein protein interaction; epidermal growth factor receptor 2; animal experiment; animal model; protein binding; antineoplastic activity; tumor regression; drug resistance, neoplasm; xenograft model antitumor assays; cell line, tumor; phosphatidylinositol 3 kinase; mice, inbred balb c; cancer inhibition; antibodies, monoclonal; mice, nude; tumor burden; membrane protein; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; immunoblotting; heat shock protein 90 inhibitor; heat shock protein 90; hsp90 heat-shock proteins; down regulation; receptor, erbb-2; binding sites; trastuzumab; lapatinib; tumor resistance; her2; 3t3 cells; snx 2112; p95-her2; protein p95; snx 5422; heterocyclic compounds with 4 or more rings
Journal Title: Oncogene
Volume: 29
Issue: 3
ISSN: 0950-9232
Publisher: Nature Publishing Group  
Date Published: 2010-01-21
Start Page: 325
End Page: 334
Language: English
DOI: 10.1038/onc.2009.337
PUBMED: 19855434
PROVIDER: scopus
PMCID: PMC3057066
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-75149123144&partnerID=40&md5=f127df0ab9c8086dec98c83eb40c0ea3
Notes: --- - "Cited By (since 1996): 9" - "Export Date: 20 April 2011" - "CODEN: ONCNE" - "Source: Scopus"
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MSK Authors
  1. Clifford Hudis
    905 Hudis
  2. Larry Norton
    758 Norton
  3. Neal Rosen
    425 Rosen
  4. David Solit
    779 Solit
  5. Sarat Chandarlapaty
    280 Chandarlapaty
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