AI Article Synopsis
- Hsp90 is crucial for stabilizing oncoproteins like HER2; this study examines the effects of the Hsp90 inhibitor IPI-504 in HER2-positive breast cancer cells resistant to trastuzumab.
- IPI-504 showed significant anti-tumor effects by reducing cell proliferation and HER2 levels in both trastuzumab-sensitive and resistant cells, suggesting its effectiveness across different cell types.
- The findings indicate that IPI-504 could be a promising new treatment option for patients with HER2-positive breast cancer who do not respond to trastuzumab therapies.
Article 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.
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| http://dx.doi.org/10.1158/1535-7163.MCT-10-0966 | DOI Listing |
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