Novel Hsp90 inhibitor FW-04-806 displays potent antitumor effects in HER2-positive breast cancer cells as a single agent or in combination with lapatinib

摘要

Human epidermal growth factor receptor 2 (HER2), a member of the HER family of tyrosine kinases and a binding partner of Heat shock protein 90 (Hsp90), is found amplifies in approximately 25% breast cancers. Treatment of HER2+ breast cancers has been greatly improved in recent years, but the accompanying upregulation of HER3 induced by HER2 blockade has subdued the therapeutic effect. FW-04-806, a novel Hsp90 N-terminal inhibitor that disassociates the Hsp90/Cdc37/client complex and degrades Hsp90 clients, was studied alone or in combination with the EGFR/HER2 tyrosine kinase inhibitor lapatinib in HER2+ breast cancer cells. We found that FW-04-806 alone or with laptinib inhibits cell proliferation, induces cell apoptosis and reduces the total and activated HER3 levels in these cells, while lapatinib has been reported to increase HER3 expression followed HER2 inhibition. The combination of FW-04-806 and lapatinib showed synergistic reduction of HER2 expression and the downstream PI3K/Akt and Ras/MEK/ERIC pathways, enhanced suppression of Akt-mediated FOXO3a inactivation and augmented antitumor efficacy on SKBR3 xenografts with a favorable toxicity profile, suggesting its viability as a combination therapy for clinical studies in HER2+ breast cancer patients. (C) 2014 Elsevier Ireland Ltd. All rights reserved.