Antitumor efficacy of IPI-504, a selective heat shock protein 90 inhibitor against human epidermal growth factor receptor 2–positive human xenograft models as a single agent and in combination with trastuzumab or lapatinib

• Published in: Molecular cancer therapeutics 2009-08, Vol.8 (8), p.2131-2141
• Main Authors: Leow, Ching Ching, Chesebrough, Jon, Coffman, Karen T, Fazenbaker, Christine A, Gooya, John, Weng, David, Coats, Steve, Jackson, Dowdy, Jallal, Bahija, Chang, Yong
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Benzoquinones - pharmacology; breast cancer; Cell Line, Tumor; Drug Screening Assays, Antitumor; Drug Synergism; HER2; Hsp90; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Lactams, Macrocyclic - pharmacology; Protein Kinase Inhibitors - pharmacology; Quinazolines - pharmacology; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; Trastuzumab; trastuzumab-resistant; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-1038

IPI-504 is a novel, highly soluble small-molecule inhibitor of heat shock protein 90 (Hsp90), a protein chaperone essential for regulating homeostasis of oncoproteins and cell signaling proteins. Human epidermal growth factor receptor 2 (HER2; ErbB2) oncoprotein, expressed in a subset of metastatic breast cancers, is a Hsp90 client protein. In this study, we investigated the antitumor activity and the mechanism of action of IPI-504 in HER2 + , trastuzumab-sensitive and trastuzumab-refractory cell lines in vitro and in vivo . IPI-504 exhibited potent antiproliferative activities (range of IC 50 , 10-40 nmol/L) against several tumor cell lines examined, whereby mechanism of action was mediated through HER2 and Akt degradation. Both intravenous and oral administration of IPI-504 assessed in multiple schedules showed potent tumor growth inhibition in vivo with corresponding degradation of HER2. The tolerability and efficacy of IPI-504 combined with either trastuzumab or lapatinib were also investigated in HER2 + tumor xenograft models. Combination of IPI-504 with trastuzumab significantly enhanced tumor growth delay and induced greater responses when compared with either agent alone. Although, as expected, trastuzumab alone did not exhibit any significant antitumor activity in the trastuzumab-resistant JIMT-1 model, IPI-504 administered in combination with trastuzumab yielded greater antitumor efficacy than either agent alone. Finally, combination of IPI-504 and lapatinib was well tolerated up to 50 mg/kg IPI-504 and 100 mg/kg lapatinib and resulted in significant delay in tumor growth, including partial and complete tumor responses. These lines of evidence support the development of IPI-504 in HER2-positive breast cancers as a single agent and in combination with either trastuzumab or lapatinib.[Mol Cancer Ther 2009;8(8):2131–41]