Fibroblast growth factor receptor-mediated signals contribute to the malignant phenotype of non-small cell lung cancer cells: therapeutic implications and synergism with epidermal growth factor receptor inhibition.
Fibroblast growth factors (FGF) and their high-affinity receptors (FGFR) represent an extensive cellular growth and survival system. Aim of this study was to evaluate the contribution of FGF/FGFR-mediated signals to the malignant growth of non-small cell lung cancer (NSCLC) and to assess their potential as targets for therapeutic interventions. Multiple FGFR mRNA splice variants were coexpressed in NSCLC cells (n = 16) with predominance of FGFR1. Accordingly, both expression of a dominant-negative FGFR1 (dnFGFR1) IIIc-green fluorescent protein fusion protein and application of FGFR small-molecule inhibitors (SU5402 and PD166866) significantly reduced growth, survival, clonogenicity, and migratory potential of the majority of NSCLC cell lines. Moreover, dnFGFR1 expression completely blocked or at least significantly attenuated s.c. tumor formation of NSCLC cells in severe combined immunodeficient mice. Xenograft tumors expressing dnFGFR1 exhibited significantly reduced size and mitosis rate, enhanced cell death, and decreased tissue invasion. When FGFR inhibitors were combined with chemotherapy, antagonistic to synergistic in vitro anticancer activities were obtained depending on the application schedule. In contrast, simultaneous blockage of FGFR- and epidermal growth factor receptor-mediated signals exerted synergistic effects. In summary, FGFR-mediated signals in cooperation with those transmitted by epidermal growth factor receptor are involved in growth and survival of human NSCLC cells and should be considered as targets for combined therapeutic approaches.
Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
Hendrik
H
Fischer
Ninon
N
Taylor
Sigrid
S
Allerstorfer
Michael
M
Grusch
Gudrun
G
Sonvilla
Klaus
K
Holzmann
Ulrike
U
Setinek
Leonilla
L
Elbling
Heidelinde
H
Cantonati
Bettina
B
Grasl-Kraupp
Christine
C
Gauglhofer
Brigitte
B
Marian
Michael
M
Micksche
Walter
W
Berger
D017398:Alternative Splicing / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology* / Q000628:therapy*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005799:Genes, Dominant; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D066246:ErbB Receptors