Antitumor activity of the Hsp90 inhibitor IPI-504 in HER2-positive trastuzumab-resistant breast cancer

Maurizio Scaltriti, Violeta Serra, Emmanuel Normant, Marta Guzman, Olga Rodriguez, Alice R. Lim, Kelly L. Slocum, Kip A. West, Varenka Rodriguez, Ludmila Prudkin, José Jimenez, Claudia Aura, José Baselga

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Abstract

Hsp90 facilitates the maturation and stability of numerous oncoproteins, including HER2. The aim of this study was to assess the antitumor activity of the Hsp90 inhibitor IPI-504 in trastuzumab-resistant, HER2-overexpressing breast cancer cells. Therapy with trastuzumab, IPI-504, and the combination of trastuzumab and IPI-504 was evaluated in trastuzumab-sensitive and trastuzumab-resistant cells. Inhibition of protein targets, cell proliferation, and tumor growth was assessed in vitro and in xenograft models. IPI-504 inhibited proliferation of both trastuzumab-sensitive and trastuzumab-resistant cells. Administration of IPI-504 markedly reduced total levels of HER2 and Akt, as well as phosphorylated Akt and mitogen-activated protein kinase (MAPK), to an equal extent in trastuzumab-sensitive and trastuzumab-resistant cells. IPI-504, used as single agent or in combination with trastuzumab, also inhibited in vivo the growth of both trastuzumab-sensitive and -resistant tumor xenografts. As a mechanism for the observed antitumor activity, IPI-504 resulted in a marked decrease in the levels of HER2, Akt, p-Akt, and p-MAPK in trastuzumab-resistant xenografts as early as 12 hours after a single dose of IPI-504. IPI-504-mediated Hsp90 inhibition may represent a novel therapeutic approach in trastuzumab refractory HER2-positive breast cancer. ©2011 AACR.
Original languageEnglish
Pages (from-to)817-824
JournalMolecular Cancer Therapeutics
Volume10
Issue number5
DOIs
Publication statusPublished - 1 May 2011

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    Scaltriti, M., Serra, V., Normant, E., Guzman, M., Rodriguez, O., Lim, A. R., Slocum, K. L., West, K. A., Rodriguez, V., Prudkin, L., Jimenez, J., Aura, C., & Baselga, J. (2011). Antitumor activity of the Hsp90 inhibitor IPI-504 in HER2-positive trastuzumab-resistant breast cancer. Molecular Cancer Therapeutics, 10(5), 817-824. https://doi.org/10.1158/1535-7163.MCT-10-0966