Abstract 4273: FGFR inhibition modulates ErbB receptor tyrosine phosphorylation in FGFR amplified cell lines.

Abstract

Abstract Fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTKs) are currently under investigation as therapeutic targets for the treatment of breast cancer. FGFR1 amplifications range from 7.5-17% in breast cancers and are associated with a shorter overall survival. FGFR1 amplified cell lines drive activation of AKT and ERK pathways and are highly sensitive to FGFR1 inhibition, suggesting an oncogenic addiction to FGFR1. FGFR2 has been reported to be activated in lapatinib-resistant, HER2-positive cells. Likewise, FGFR3 expression levels are often elevated in tamoxifen-resistant, ER positive patients. FGFR 4 overexpression correlated with poor response to chemotherapy due to activation of MAPK and increase in B-cell lymphoma extra large (BCL-XL) levels. Using a highly sensitive, novel proximity mediated immuno-microarray, Collaborative Enzyme Enhanced Reactive-immunoassay (CEERTM), this study seeks to determine whether FGFR signal transduction pathway inhibition modulate ErbB receptor tyrosine kinases and AKT/ERK signal transduction pathway in cell lines expressing varying levels of FGFR and ErbB receptors. FGFR 1, 2, 3, and 4 amplified cell lines (MDA-MB-134VI (KRAS), SNU16, RT112, and MDA-MB-453) were individually treated with varying dosages (1, 10, 100, and 1000nM) of pan FGFR inhibitors (AZD4547 and Ponatinib-AP24534) in presence of corresponding FGF ligand (FGF1, FGF7, FGF9, and FGF19). Expression and activation of FGFR 1, 2, 3, 4 and EGFR, HER2, HER3, HER4 and downstream signaling proteins FRS2, AKT, ERK, MEK, and RSK were measured utilizing CEERTM. Both FGFR inhibitors sufficiently inhibited phosphorylation of FGFRs in each of the four FGFR amplified cell line. In MDA-MB-453, FGFR4 inhibition increased phosphorylation of HER2, and HER3 along with AKT. In MDA-MB-134, FGFR1 inhibition decreased levels of HER3 phosphorylation along with reduction in phosphorylated ERK, MEK, and RSK. In SNU16, FGFR2 inhibition led to a decrease in EGFR, HER2, and HER3 phosphorylation along with reduction in phosphorylated MEK, ERK, and RSK. Analysis of RT112 and additional cell lines with varying levels of ErbB and FGFR receptor tyrosine kinases are currently in progress. Our data suggests that FGFR inhibition may modulate parallel / compensatory ErbB and other signaling pathway as observed in this study. Utilizing CEERTM, comprehensive profiling may provide unique insight into potential feedback mechanisms in each patient and evidence for rational selection of appropriate combinational therapies. Citation Format: Nicholas Hoe, Kelly Jin, Yating Ma, Crystal Kuy, Michael Mateling, JinYao Zhou, Richard Kirkland, Saswati Hazara, Phillip Kim, Xinjun Liu, Sharat Singh. FGFR inhibition modulates ErbB receptor tyrosine phosphorylation in FGFR amplified cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4273. doi:10.1158/1538-7445.AM2013-4273