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Molecular Pharmacology Fast Forward
First published on October 10, 2008; DOI: 10.1124/mol.108.049544

0026-895X/09/7501-196-207$20.00
Mol Pharmacol 75:196-207, 2009

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

Lindsay Marek, Kathryn E. Ware, Alexa Fritzsche, Paula Hercule, Wallace R. Helton, Jennifer E. Smith, Lee A. McDermott, Christopher D. Coldren, Raphael A. Nemenoff, Daniel T. Merrick, Barbara A. Helfrich, Paul A. Bunn, Jr., and Lynn E. Heasley

Departments of Craniofacial Biology (L.M., K.E.W., A.F., P.H., J.E.S., L.E.H.), Medicine (C.D.C., R.A.N., B.A.H., P.A.B.), Pharmacology (W.R.H.), and Pathology (D.T.M.), University of Colorado Cancer Center (C.D.C., R.A.N., B.A.H., P.A.B., L.E.H.), University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado; and Hoffmann-La Roche Inc., Nutley, New Jersey (L.A.M.)

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.

Received June 7, 2008; accepted October 9, 2008

Address correspondence to: Dr. Lynn E. Heasley, Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Denver Anschutz Medical Campus, Mail Stop 8120, P.O. Box 6511, Aurora, CO 80045. E-mail: lynn.heasley{at}ucdenver.edu






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