Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer

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. Mol Cancer Ther; 10(5); 817-24. Ó2011 AACR.

Molecular Pathways: Targeting Hsp90—Who Benefits and Who Does Not

“…Estrogen and progesterone receptors are key drivers of breast cancer and are known to be client proteins of Hsp90 (12,13). Furthermore, ERBB2, a receptor tyrosine kinase that is overexpressed in 20% of breast cancers, is also among the most sensitive client proteins of Hsp90, with shown preclinical activity of Hsp90 inhibitors in ERBB2-driven xenograft models (42,43). In hormone-sensitive metastatic prostate cancer, androgen deprivation still is the mainstay of treatment and, given that the androgen receptor is a known client of Hsp90, inhibition of this chaperone may have a potential role in the management of this malignancy (44,45).…”

Heat Shock Protein 90 Is a Potential Therapeutic Target in Cholangiocarcinoma

“…Inhibiting HSP90 downregulates the phosphatidylinositide-3-kinase pathway, which is due (at least in part) to the degradation of AKT and its upstream effectors (e.g., EGFR and HER2; refs. 33,34). Moreover, a previous study shows that NVP-AUY922 has an antiangiogenic effect on pancreatic cancer cells.…”

-Lapachone Induces NAD(P)H:Quinone Oxidoreductase-1- and Oxidative Stress-Dependent Heat Shock Protein 90 Cleavage and Inhibits Tumor Growth and Angiogenesis

“…Based on the results obtained from our human lung cancer xenograft mouse model, we believe that b-lap targets multiple pivotal points in both tumor cells and endothelial cells, providing a combinatorial blockade of the hallmark phenotypic features of malignancy. Recently, promising activity was reported with 17-AAG in combination with trastuzumab in HER2-positive breast cancer refractory to trastuzumab therapy (Scaltriti et al, 2011), indicating that Hsp90 inhibitors may overcome drug resistance. By considering the low toxicity of b-lap in clinical trials, and on the basis of preclinical results that we obtained in our xenograft mice, we postulate that the combination of b-lap with a molecule-targeted agent, such as the epidermal growth factor receptor inhibitor gefitinib, the HER2 inhibitor trastuzumab, or the VEGFR inhibitor bevacizumab, should have a greater therapeutic potential in clinical applications.…”