Investigation of the mechanism of gefitinib resistance by comprehensive genetic analysis

• Project/Area Number: 24790822
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Keio University
• Principal Investigator: TERAI Hideki 慶應義塾大学, 医学部, 助教 (50445293)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: EGFR-TKI / 肺癌 / 薬剤耐性 / イレッサ / ゲフィチニブ / 獲得耐性 / FGF2 / FGFR1 / FGFR / EGFR-TKI耐性化 / DNAメチル化 / エピジェネティクス

Research Abstract

Almost all patients with non-small cell lung cancer who harbor an epidermal growth factor receptor (EGFR) mutation initially respond well to EGFR-tyrosine kinase inhibitors (TKIs) eventually experience relapse. In this study, we have established a gefitinib-resistant cell line model by long-term exposure to gefitinib. We used originally gefitinib-sensitive lung cancer cell lines, namely PC9 and HCC827. We found that the expressions of both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells compared to those in PC9 naïve (PC9 na) cells. We found that proliferation of the PC9 GR cells was dependent on FGF2-FGFR1 pathway. Inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored the gefitinib sensitivity in PC9 GR cells. We propose FGF2-FGFR1 activation through autocrine loop is a novel mechanism of acquiring resistance to EGFR-TKIs and that this loop be targeted to overcome acquired resistance to EGFR-TKIs in a subset of NSCLC patients.

Research Products

• [Journal Article] Activation of the FGF2-FGFR1 Autocrine Pathway: A Novel Mechanism of Acquired Resistance to Gefitinib in NSCLC Cells. (2013)
  • Author(s): Terai H, Soejima K, Yasuda H, et al
  • Journal Title: Mol Cancer Res Volume: 印刷中 Issue: 7 Pages: 759-767
  • DOI: 10.1158/1541-7786.mcr-12-0652
  • Peer Reviewed
• [Journal Article] Activation of the FGF2-FGFR1 Autocrine Pathway: A Novel Mechanism of Acquired Resistance to Gefitinib in NSCLC Cells. (2013)
  • Author(s): Terai H, Soejima KN, Yasuda H, Nakayama S, Hamamoto J, Arai D, Ishioka K, Ohgino K, Ikemura S, Sato T, Yoda S, Satomi R, Naoki K, Betsuyaku T.
  • Journal Title: Molecular Cancer Research Volume: 未定
  • Peer Reviewed
• [Presentation] Kenzo Soejima, Katsuhiko Naoki et al. Activation of FGF2-FGFR1 pathway in EGFR-mutant lung cancer cell line with long-term gefitinib exposure (2013)
  • Author(s): Hideki Terai
  • Organizer: 103th AACR annual meeting
  • Place of Presentation: Washington, DC.
• [Presentation] Activation of FGF2-FGFR1 pathway in EGFR-mutant lung cancer cell line with long-term gefitinib exposure. (2013)
  • Author(s): H. Terai, K. Soejima, K. Naoki, H. Yasuda, R. Satomi, S. Nakayama, S.Yoda, S. Ikemura, T. Sato, K. Ishioka, D. Arai, K. Ohgino, J. Hamamoto, T. Betsuyaku
  • Organizer: 2013 AACR annual meeting
  • Place of Presentation: Washington, DC, USA
• [Presentation] Kenzo Soejima, Katsuhiko Naoki, etal. Activation of FGF2-FGFR1 pathway in EGFR-mutant lung cancer cell line with long-term gefitinib exposure. (2012)
  • Author(s): Hideki Terai
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
• [Presentation] Activation of FGF2-FGFR1 pathway in EGFR-mutant lung cancer cell line with long-term gefitinib exposure. (2012)
  • Author(s): 寺井秀樹、副島研造、猶木克彦、安田浩之、池村辰之介、佐藤崇、荒井大輔、石岡宏太、扇野圭子、濱本純子、別役智子
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌・ホテルロイトン札幌
• [Presentation] Activation of FGF2-FGFR1 pathway in EGFR-mutant lung cancer cell line with long-term gefitinib exposure.
  • Author(s): Hideki Terai
  • Organizer: 2013 104th AACR Annual Meeting
  • Place of Presentation: Washington D. C. Convention Center
• [Presentation] Aberrant DNA methylation and expression of mRNA in EGFR-mutant lung cancer cell line with long-term exposure to gefitinib
  • Author(s): Hideki Terai
  • Organizer: 2014 105th AACR Annual Meeting
  • Place of Presentation: San Diego Convention Center