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Dominant FGF Autocrine Signaling in Gefitinib‐Resistant Non‐Small Cell Lung Cancer Cells
Author(s) -
Heasley Lynn E,
Marek Lindsay,
Fritzsche Alexa,
Helton Wallace R,
Nemenoff Raphael A,
McDermott Lee A,
Helfrich Barbara,
Bunn Paul A.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.820.7
Subject(s) - autocrine signalling , gefitinib , fibroblast growth factor , fibroblast growth factor receptor , fibroblast growth factor receptor 1 , cancer research , fgf9 , mapk/erk pathway , biology , receptor tyrosine kinase , tyrosine kinase , cell growth , microbiology and biotechnology , epidermal growth factor receptor , receptor , signal transduction , biochemistry
The frequent intrinsic resistance of non‐small cell lung cancers (NSCLC) to EGF receptor (EGFR)‐specific tyrosine kinase inhibitors (TKIs) such as gefitinib limits their effectiveness as therapeutics. We tested the hypothesis that autocrine growth signaling through one or more distinct receptor tyrosine kinases occurs in NSCLC cells. Gene expression array data indicated 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 were frequently co‐expressed. Specific silencing of FGF2 or expression of a dominant‐negative FGFR1 construct reduced proliferation and anchorage‐independent growth of H226 cells that secrete high levels of FGF2 and express both FGFR1 and FGFR2. Moreover, a TKI (RO4383596) that targets FGFRs inhibited basal ERK signaling as a measure of FGFR signaling as well as anchorage‐independent growth of NSCLC cell lines that co‐express FGF2 or FGF9 and FGFRs. By contrast, gefitinib‐sensitive NSCLC cell lines expressed little or no FGF2, FGF9, FGFR1 IIIc or FGFR2 IIIc. In addition, RO4383596 exerted no effect on basal ERK activity or anchorage‐independent growth of these cell lines. Thus, we propose that a growth factor autocrine loop involving FGF2, FGF9 and their respective high‐affinity FGFRs is dominant in gefitinib‐resistant NSCLC.