Received for publication June 9, 2008.
Revised September 18, 2008.
Accepted for publication October 9, 2008.

Fibroblast Growth Factor (FGF) and FGF Receptor-Mediated Autocrine Signaling in Non-Small Cell Lung Cancer Cells

Abstract

Despite widespread expression of EGF receptors (EGFRs) and EGF family ligands in non-small cell lung cancer (NSCLC), EGFR-specific tyrosine kinase inhibitors (TKIs) such as gefitinib exhibit limited activity in this cancer. We propose that autocrine growth signaling pathways distinct from EGFR are active in NSCLC cells. To this end, gene expression profiling revealed frequent co-expression of specific fibroblast growth factors (FGFs) and FGF receptors (FGFRs) in NSCLC cell lines. Notably, FGF2 and FGF9 as well as FGFR1 IIIc and/or FGFR2 IIIc mRNA and protein are frequently co-expressed in NSCLC cell lines, especially those that are insensitive to gefitinib. Specific silencing of FGF2 reduced anchorage-independent growth of two independent NSCLC cell lines that secrete FGF2 and co-express FGFR1 IIIc and/or FGFR2 IIIc. Moreover, a TKI (RO4383596) that targets FGFRs inhibited basal FRS2 and ERK phosphorylation, two measures of FGFR activity, as well as proliferation and anchorage-independent growth of NSCLC cell lines that co-express FGF2 or FGF9 and FGFRs. By contrast, RO4383596 influenced neither signal transduction nor growth of NSCLC cell lines lacking FGF2, FGF9, FGFR1 or FGFR2 expression. Thus, FGF2, FGF9 and their respective high-affinity FGFRs comprise a growth factor autocrine loop that is active in a subset of gefitinib-insensitive NSCLC cell lines.

Key words: FGF, MAP Kinase, Oncogenes