title: 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.
abstract: 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/ERK 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.
authors.affiliation: School of Pharmacy, Fujian Medical University, Fuzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Fujian Medical University, Fuzhou, China.
authors.forename: Qun-Dan
authors.initials: QD
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Fujian Medical University, Fuzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Fujian Medical University, Fuzhou, China.
authors.forename: Ying-Li
authors.initials: YL
authors.lastname: Kong
authors.affiliation: School of Pharmacy, Fujian Medical University, Fuzhou, China.
authors.forename: Pin-Rong
authors.initials: PR
authors.lastname: Cao
authors.affiliation: School of Pharmacy, Fujian Medical University, Fuzhou, China; Fujian Institute of Microbiology, Fuzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: School of Pharmacy, Fujian Medical University, Fuzhou, China; Fuijan Provincial Key Laboratory of Natural Medicine Pharmacology, Fuzhou, China. Electronic address: xjh@mail.fjmu.edu.cn.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Fujian Medical University, Fuzhou, China; Fuijan Provincial Key Laboratory of Natural Medicine Pharmacology, Fuzhou, China. Electronic address: yeminkobe@hotmail.com.
authors.forename: Min
authors.initials: M
authors.lastname: Ye
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D000077341:Lapatinib; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010080:Oxazoles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D000077341:Lapatinib; D010080:Oxazoles; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C022800:conglobatin; C508053:ERBB2 protein, human
keywords: FW-04-806; HER2; HER2-positive breast cancer; HER3