TY - JOUR
T1 - Activation of the FGF2-FGFR1 autocrine pathway
T2 - A novel mechanism of acquired resistance to gefitinib in NSCLC
AU - Terai, Hideki
AU - Soejima, Kenzo
AU - Yasuda, Hiroyuki
AU - Nakayama, Sohei
AU - Hamamoto, Junko
AU - Arai, Daisuke
AU - Ishioka, Kota
AU - Ohgino, Keiko
AU - Ikemura, Shinnosuke
AU - Sato, Takashi
AU - Yoda, Satoshi
AU - Satomi, Ryosuke
AU - Naoki, Katsuhiko
AU - Betsuyaku, Tomoko
PY - 2013/7
Y1 - 2013/7
N2 - Patients with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutations initially respond to EGFR-tyrosine kinase inhibitors (TKI) but eventually experience relapse. Acquired resistance to EGFR-TKIs is strongly associated with patient mortality. Thus, elucidation of the mechanism of acquired resistance to EGFR-TKIs is of great importance. In this study, gefitinib-resistant cell line models were established by long-term exposure to gefitinib using the gefitinib-sensitive lung cancer cell lines, PC9 and HCC827. Expression analyses indicated that both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells as compared with PC9 naïve (PC9 na) cells. Importantly, proliferation of gefitinib-resistant cells was dependent on the FGF2-FGFR1 pathway. Mechanistically, inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored gefitinib sensitivity in PC9 GR cells. These data suggest that FGF2-FGFR1 activation through an autocrine loop is a novel mechanism of acquired resistance to EGFR-TKIs.
AB - Patients with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutations initially respond to EGFR-tyrosine kinase inhibitors (TKI) but eventually experience relapse. Acquired resistance to EGFR-TKIs is strongly associated with patient mortality. Thus, elucidation of the mechanism of acquired resistance to EGFR-TKIs is of great importance. In this study, gefitinib-resistant cell line models were established by long-term exposure to gefitinib using the gefitinib-sensitive lung cancer cell lines, PC9 and HCC827. Expression analyses indicated that both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells as compared with PC9 naïve (PC9 na) cells. Importantly, proliferation of gefitinib-resistant cells was dependent on the FGF2-FGFR1 pathway. Mechanistically, inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored gefitinib sensitivity in PC9 GR cells. These data suggest that FGF2-FGFR1 activation through an autocrine loop is a novel mechanism of acquired resistance to EGFR-TKIs.
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UR - http://www.scopus.com/inward/citedby.url?scp=84880547779&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-12-0652
DO - 10.1158/1541-7786.MCR-12-0652
M3 - Article
C2 - 23536707
AN - SCOPUS:84880547779
SN - 1541-7786
VL - 11
SP - 759
EP - 767
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 7
ER -
