PT  - JOURNAL ARTICLE
AU  - Lindsay Marek
AU  - Kathryn E. Ware
AU  - Alexa Fritzsche
AU  - Paula Hercule
AU  - Wallace R. Helton
AU  - Jennifer E. Smith
AU  - Lee A. McDermott
AU  - Christopher D. Coldren
AU  - Raphael A. Nemenoff
AU  - Daniel T. Merrick
AU  - Barbara A. Helfrich
AU  - Paul A. Bunn, Jr.
AU  - Lynn E. Heasley
TI  - Fibroblast Growth Factor (FGF) and FGF Receptor-Mediated Autocrine Signaling in Non-Small-Cell Lung Cancer Cells
AID  - 10.1124/mol.108.049544
DP  - 2009 Jan 01
TA  - Molecular Pharmacology
PG  - 196--207
VI  - 75
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/75/1/196.short
4100  - http://molpharm.aspetjournals.org/content/75/1/196.full
SO  - Mol Pharmacol2009 Jan 01; 75
AB  - Despite widespread expression of epidermal growth factor (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 coexpression of specific fibroblast growth factors (FGFs) and FGF receptors (FGFRs) in NSCLC cell lines. It is noteworthy that FGF2 and FGF9 as well as FGFR1 IIIc and/or FGFR2 IIIc mRNA and protein are frequently coexpressed 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 coexpress FGFR1 IIIc and/or FGFR2 IIIc. Moreover, a TKI [(±)-1-(anti-3-hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido-[4,5-d]pyrimidin-2-one (RO4383596)] that targets FGFRs inhibited basal FRS2 and extracellular signal-regulated kinase phosphorylation, two measures of FGFR activity, as well as proliferation and anchorage-independent growth of NSCLC cell lines that coexpress 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. The American Society for Pharmacology and Experimental Therapeutics