Fibroblast Growth Factor Receptors Are Components of Autocrine Signaling Networks in Head and Neck Squamous Cell Carcinoma Cells

Abstract

Purpose We previously reported that a fibroblast growth factor (FGF) receptor (FGFR) signaling pathway drives growth of lung cancer cell lines of squamous and large cell histologies. Herein, we explored FGFR dependency in cell lines derived from the tobacco-related malignancy, head and neck squamous cell carcinoma (HNSCC). Experimental Design FGF and FGFR mRNA and protein expression was assessed in nine HNSCC cell lines. Dependence on secreted FGF2 for cell growth was tested with FP-1039, an FGFR1-Fc fusion protein. FGFR and EGFR-dependence was defined by sensitivity to multiple inhibitors selective for FGFRs or EGFR. Results FGF2 was expressed in eight of the nine HNSCC cell lines examined. Also, FGFR2 and FGFR3 were frequently expressed while only two lines expressed FGFR1. FP-1039 inhibited growth of HNSCC cell lines expressing FGF2, identifying FGF2 as an autocrine growth factor. FGFR inhibitors selectively reduced in vitro growth and ERK signaling in three HNSCC cell lines while three distinct lines exhibited responsiveness to both EGFR and FGFR inhibitors. Combinations of these drugs yielded additive growth inhibition. Finally, three cell lines were highly sensitive to EGFR TKIs with no contribution from FGFR pathways. Conclusions FGFR signaling was dominant or co-dominant with EGFR in six HNSCC lines while three lines exhibited little or no role for FGFRs and were highly EGFR-dependent. Thus, the HNSCC cell lines can be divided into subsets defined by sensitivity to EGFR and FGFR-specific TKIs. FGFR inhibitors may represent novel therapeutics to deploy alone or in combination with EGFR inhibitors in HNSCC.

FGFR a promising druggable target in cancer: Molecular biology and new drugs

“…Several different mAb have been developed to target components of the FGF-FGFR axis: GP369 (Bai et al, 2010), GAL-FR21 (Zhao et al, 2010), GAL-FR22 (Inokuchi et al, 2015), GAL-F2 , MFGR1877S (Fauvel and Yasri, 2014), hLD1.vb (Bumbaca et al, 2011), FP-1039(Marshall et al, 2011, R3Mab (French et al, 2012), PRO-001 (French et al, 2012), 1A6 (Pai et al, 2008) and LD1 (French et al, 2012). Two main mechanisms of action have been considered; either blocking ligand binding (trap-ligand) or preventing receptor dimerization.…”

Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

“…CONCERT-1; NCT00547157), are also underway. High expression of fibroblast growth factor receptors (FGFRs) have been identified in SCCHN [83,84], and demonstrated to be associated with poor clinical outcome [84], thus identifying FGFR as another potential therapeutic target in patients with SCCHN. Targeting AKT and MEK, downstream effectors of the PI3K/AKT and MAPK pathways, respectively, in combination may provide a molecular therapeutic target for RAS-driven tumorigenesis in oral cancer [85].…”

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

“…Similar results were obtained for human head and neck squamous carcinoma cell lines. Indeed, FGF2 and FGFR coexpression frequently occurs in these cells, leading to an autocrine loop of stimulation that may involve also EGFR activation [77]. Several FGFs, including FGF1, FGF2, FGF5, FGF6, FGF7, FGF8, FGF9, FGF10, FGF17, FGF18 and FGF19 are upregulated in human prostate cancer [38] and murine studies have demonstrated the complex FGF/FGFR-dependent interplay between the epithelial and mesenchymal compartments in these tumors [78].…”