FGFR and FGF ligand overexpression in lung cancer: Implications for targeted therapy.

11080 Background: Fibroblast growth factor receptors (FGFR) have been shown to be frequently dysregulated in non-small cell lung cell carcinoma (NSCLC). To determine the impact of dysregulation of FGFR pathway in NSCLC, we profiled 100 samples using a sensitive gene expression assay for FGFR and its ligands. Methods: FGFR and FGF gene expression in formalin fixed paraffin embedded (FFPE) samples was performed using a sensitive quantitative nuclease protection assay. This gene expression panel includes all four FGFRs, all 22 FGF ligands and known FGF interacting proteins KLOTHO and KLOTHO beta. Using this array we profiled 100 NSCLC samples (45 squamous, 55 non-squamous). Results: Gene expression analysis of the FGFR family in lung cancer showed overexpression by 3X over median levels of FGFR2 and FGFR3 predominantly in squamous subtype (28% and 19% respectively), FGFR4 overexpresion mainly in non-squamous subtype (25%) and FGFR1 overexpression evenly distributed between squamous and non-squamous subtypes (9 %). There were rare instances of joint overexpression of more than one FGFR, FGFR 1 and 2 together (6%), FGFR 1 and 3 together (2%) and FGFR 3 and 4 together (2%). Overexpression of FGFs was seen in ~35% of all NSCLC samples with FGF19 overexpression being the most common, with increases seen in 20 % of all NSCLC samples. Conclusions: We report for the first time a sensitive and comprehensive FGF and FGFR gene expression analysis of 100 lung cancers. Our expression profiling did not confirm frequent overexpression of FGFR1 in squamous NSCLC in contradiction to frequent gene amplification at this locus suggesting that DNA amplification may not result in transcriptional alteration in many cases. Additionally, we detected frequent overexpression of FGFR2 and 3 in squamous NSCLC and FGFR4 overexpression in adenocarcinoma subtype of NSCLC. The receptor overexpression is frequently associated with overexpression of FGF ligands suggesting a paracrine effect. Expression profiling data support frequent FGFR pathway dysregulation in lung cancer and highlight that gene expression profiling is an important modality for identifying potential responders to novel anti-FGFR therapies.