Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis
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Dey, Julien H, Bianchi, Fabrizio, Voshol, Johannes, Bonenfant, Debora, Oakeley, Edward J, Hynes, Nancy E and Imark, Esther (2010) Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis. Cancer Research, 70 (10). pp. 4151-4162. ISSN 0008-5472
Abstract
Members of the fibroblast growth factor receptor (FGFR) family have essential roles in normal physiology and in cancer where they control diverse processes. FGFRs have been associated with breast cancer development and models to study their role in cancer and their targeting potential are desirable. Here, we present an in vitro and in vivo analysis of FGFRs in the mammary cancer cell lines 67NR and 4T1. We show that both cell lines co-express FGFRs and ligands and display autocrine FGFR signaling activity. Fibroblast growth factor receptor substrate 2 (FRS2), a downstream mediator of FGFR is constitutively tyrosine-phosphorylated and multiple signaling pathways are active. Treatment of 67NR and 4T1 cultures with TKI258, a selective FGFR tyrosine kinase inhibitor caused a rapid decrease in FRS2 phosphorylation, decreased the activity of ERK1/2, AKT and PLC and blocked proliferation and induced 4T1 apoptotic cell death via blockade of the PI3K/AKT pathway. In vivo, one dose of TKI258 rapidly lowered FRS2 phosphorylation and ERK1/2 and AKT activity in mammary tumors. Long-term treatment of 4T1 and 67NR tumor-bearing mice had a significant impact on primary tumor outgrowth and 4T1 tumor induced lung metastases. A microarray analyses was carried out to identify prognostic markers in human breast tumors and targets with roles in TKI258- anti-tumor activity. Of interest are the down-regulated matrix metalloproteases (MMP), in particular MMP-9, which is essential for metastatic spread of 4T1 tumors.
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| Date Deposited: | 13 Oct 2015 13:16 |
| Last Modified: | 13 Oct 2015 13:16 |
| URI: | https://oak.novartis.com/id/eprint/2040 |