Activation of the FGF2-FGFR1 autocrine pathway: A novel mechanism of acquired resistance to gefitinib in NSCLC

Hideki Terai, Kenzo Soejima, Hiroyuki Yasuda, Sohei Nakayama, Junko Hamamoto, Daisuke Arai, Kota Ishioka, Keiko Ohgino, Shinnosuke Ikemura, Takashi Sato, Satoshi Yoda, Ryosuke Satomi, Katsuhiko Naoki, Tomoko Betsuyaku

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)759-767
Number of pages9
JournalMolecular Cancer Research
Volume11
Issue number7
DOIs
Publication statusPublished - 2013 Jul 1

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Terai, H., Soejima, K., Yasuda, H., Nakayama, S., Hamamoto, J., Arai, D., Ishioka, K., Ohgino, K., Ikemura, S., Sato, T., Yoda, S., Satomi, R., Naoki, K., & Betsuyaku, T. (2013). Activation of the FGF2-FGFR1 autocrine pathway: A novel mechanism of acquired resistance to gefitinib in NSCLC. Molecular Cancer Research, 11(7), 759-767. https://doi.org/10.1158/1541-7786.MCR-12-0652