Overcoming epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs)-resistance in lung cancer through PI3-kinase pathway

• Project/Area Number: 23501311
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Clinical oncology
• Research Institution: Keio University
• Principal Investigator: NAOKI Katsuhiko 慶應義塾大学, 医学部, 講師 (40265806)
• Co-Investigator(Renkei-kenkyūsha): SOEJIMA Kenzo 慶應義塾大学, 医学部, 准教授 (30236145) ; IKEMURA Shinnosuke 慶應義塾大学, 医学部, 助教 (30445291)
• Research Collaborator: HAMAMOTO Junko 慶應義塾大学, 医学部, 助教 (40570239)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 耐性肺癌 / 上皮成長因子受容体阻害剤 / 線維芽細胞増殖因子 / 分子標的治療 / 繊維芽細胞増殖因子 / PI3キナーゼ

Research Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have great effect in the treatment of lung cancer patients with EGFR mutation. But many of the patients eventually get worsened (become 'resistance') within one year. It is important to overcome the 'EGFR-TKI-resistance'.
Using lung cancer cell lines, we had elucidated that fibroblast growth factors (FGFs) and receptors (FGFRs) had related to the EGFT-TKI resistance. Using clinical specimens, high FGF9 expression is related to poor prognosis in lung cancer patients. Overexpression of FGF in lung epithelial cell induced transformation, and the tumor formation in immune-deficient mouse was accelerated. FGFR-inhibitor blocked that tumor formation. Using cell lines and clinical specimens, we have comprehensively revealed that FGF/FGFR pathway has an important role in prognosis, tumor formation, and resistance in lung cancer, suggesting that FGF/FGFR pathway can be possible drug target.

Research Products

• [Journal Article] Expression of fibroblast growth factor 9 is associated with poor prognosis in patients with resected non-small cell lung cancer. (2014)
  • Author(s): Ohgino K, Soejima K, Yasuda H, Hayashi Y, Hamamoto J, Naoki K, Arai D, Ishioka K, Sato T, Terai H, Ikemura S, Yoda S, Tani T, Kuroda A, Betsuyaku T.
  • Journal Title: Lung Cancer Volume: 83 Issue: 1 Pages: 90-6
  • DOI: 10.1016/j.lungcan.2013.10.016
  • Peer Reviewed
• [Journal Article] Identification of microRNAs differentially expressed between lung squamous cell carcinoma and lung adenocarcinoma (2013)
  • Author(s): Hamamoto J, Soejima K, Yoda S, Naoki K, Nakayama S, Satomi R, Terai H, Ikemura S, Sato T, Yasuda H, Hayashi Y, Sakamoto M, Takebayashi T, Betsuyaku T
  • Journal Title: Molecular Medicine Reports Volume: 8(2) Issue: 2 Pages: 456-462
  • DOI: 10.3892/mmr.2013.1517
  • 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 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] 肺癌における最新の分子標的治療 (2013)
  • Author(s): 猶木克彦
  • Journal Title: 東京内科医会会誌 Volume: 28巻3号 Pages: 248-253
• [Journal Article] 肺癌治療の進歩 EGFR 阻害剤を使いこなす (2013)
  • Author(s): 猶木克彦
  • Journal Title: 日本呼吸ケア・リハビリテーション学会誌 Volume: 23巻3号 Pages: 274-278
  • NAID: 130005123216
• [Presentation] EXPRESSION OF FIBROBLAST GROWTH FACTOR-9 IS ASSOCIATED WITH POOR PROGNOSIS OF RESECTED NON-SMALL CELL LUNG CANCER PATIENTS (2013)
  • Author(s): Keiko Ohgino, Kenzo Soejima, Hiroyuki Yasuda, Yuichiro Hayashi, Tetsuo Tani, Aoi Kuroda, Daisuke Arai, Kota Ishioka, Takashi Sato, Hideki Terai, Shinnosuke Ikemura, Sohei Nakayama, Satoshi Yoda, Junko Hamamoto, Katsuhiko Naoki, Tomoko Betsuyaku
  • Organizer: 第15回世界肺癌学会総会
  • Place of Presentation: オーストラリア(シドニー)
  • Year and Date: 2013-10-29
• [Presentation] CHARACTERISTICS OF RE-BIOPSIED NSCLC PATIENTS WITH ACQUIRED RESISTANCE TO EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS (2013)
  • Author(s): Daisuke Arai, Kenzo Soejima, Hiroyuki Yasuda, Tetsuo Tani, Aoi Kuroda, Kota Ishioka, Keiko Ohgino, Takashi Sato, Hideki Terai, Shinnosuke Ikemura, Junko Hamamoto, Katsuhiko Naoki, Yuichiro Hayashi, Tomoko Betsuyaku
  • Organizer: 第15回世界肺癌学会総会
  • Place of Presentation: オーストラリア(シドニー)
  • Year and Date: 2013-10-28
• [Presentation] EGFR-TKI 耐性化後に再生検を行った非小細胞肺癌17例の検討 (2013)
  • Author(s): 荒井大輔,副島研造,猶木克彦,石岡宏太,扇野圭子,佐藤崇,安田浩之,林雄一郎,別役智子
  • Organizer: 第11回日本臨床腫瘍学会学術総会
  • Place of Presentation: 仙台
  • Year and Date: 2013-08-31
• [Presentation] FGF9 が肺胞上皮細胞株および肺癌細胞株に及ぼす影響の検討 (2013)
  • Author(s): 石岡宏太、副島研造、猶木克彦、黒田葵、荒井大輔
  • Organizer: 第17回日本がん分子標的治療学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2013-06-13
• [Presentation] Activation of FGF2-FGFR1 pathway in EGFR-mutant lung cancer cell line with long-term gefitinib exposure (2013)
  • Author(s): Terai H, Soejima K, Naoki K, Yasuda H, Satomi R, Nakayama S, Yoda S, Ikemura S, Sato T, Ishioka K, Arai D, Ohgino K, Tani T, Kuroda A, Hamamoto J, Betsuyaku TTerai H, Soejima K, Naoki K, Yasuda H, Satomi R, Nakayama S, Yoda S, Ikemura S, Sato T, Ishioka K, Arai D, Ohgino K, Tani T, Kuroda A, Hamamoto J, Betsuyaku T
  • Organizer: 2013 AACR Annual Meeting
  • Place of Presentation: USA (Washington DC)
  • Year and Date: 2013-04-10
• [Presentation] FGF9 overexpression promotes tumorigenic potential of non-small cell lung cancer (NSCLC) cells, and is associated with poor prognosis in NSCLC patients (2013)
  • Author(s): Kota Ishioka, Kenzo Soejima, Hiroyuki Yasuda, Keiko Ohgino, Satoshi Yoda, Takashi Sato, Junko Hamamoto, Daisuke Arai, Tetsuo Tani, Aoi Kuroda, Katsuhiko Naoki, Tomoko Betsuyaku
  • Organizer: 2013 AACR Annual Meeting
  • Place of Presentation: USA (Washington DC)
  • Year and Date: 2013-04-10
• [Presentation] EGFR-TKI 耐性化後の再生検により扁平上皮癌と診断したNSCLC-NOS の2 例 (2013)
  • Author(s): 荒井大輔、黒田葵、谷哲夫、持丸貴生、扇野圭子、佐々木衛、石岡宏太、田中希宇人、安田浩之、石井誠、福永興壱、猶木克彦、田坂定智、副島研造、林雄一郎、別役智子
  • Organizer: 第166回日本肺癌学会関東支部会
  • Place of Presentation: 東京
  • Year and Date: 2013-03-16
• [Presentation] EXPRESSION OF FIBROBLAST GROWTH FACTOR-9 IS ASSOCIATED WITH POOR PROGNOSIS OF RESECTED NON-SMALL CELL LUNG CANCER PATIENTS (2013)
  • Author(s): Keiko Ohgino, Kenzo Soejima, Hiroyuki Yasuda, Yuichiro Hayashi, Tetsuo Tani, Aoi Kuroda, Daisuke Arai, Kota Ishioka, Takashi Sato, Hideki Terai, Shinnosuke Ikemura, Sohei Nakayama, Satoshi Yoda, Junko Hamamoto, Katsuhiko Naoki, Tomoko Betsuyaku
  • Organizer: 第15回世界肺癌学会総会
  • Place of Presentation: オーストラリア（シドニー）
• [Presentation] CHARACTERISTICS OF RE-BIOPSIED NSCLC PATIENTS WITH ACQUIRED RESISTANCE TO EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS (2013)
  • Author(s): Daisuke Arai, Kenzo Soejima, Hiroyuki Yasuda, Tetsuo Tani, Aoi Kuroda, Kota Ishioka, Keiko Ohgino, Takashi Sato, Hideki Terai, Shinnosuke Ikemura, Junko Hamamoto, Katsuhiko Naoki, Yuichiro Hayashi, Tomoko Betsuyaku
  • Organizer: 第15回世界肺癌学会総会
  • Place of Presentation: オーストラリア（シドニー）
• [Presentation] EGFR-TKI耐性化後に再生検を行った非小細胞肺癌17例の検討 (2013)
  • Author(s): 荒井大輔，副島研造，猶木克彦，石岡宏太，扇野圭子，佐藤崇，安田浩之，林雄一郎，別役智子
  • Organizer: 第11回日本臨床腫瘍学会学術総会
  • Place of Presentation: 仙台
• [Presentation] FGF9が肺胞上皮細胞株および肺癌細胞株に及ぼす影響の検討 (2013)
  • Author(s): 石岡宏太、副島研造、猶木克彦、黒田葵、荒井大輔
  • Organizer: 第17回日本がん分子標的治療学会学術集会
  • Place of Presentation: 京都
• [Presentation] 長期ゲフィチニブ曝露によるEGFR 変異肺癌細胞株におけるFGF2-FGFR1 経路の活性化 (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、浜本純子、別役智子
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-20
• [Presentation] Expression of fibroblast growth factor-9 is associated with poor prognosis of resected non-small cell lung cancer patients (2012)
  • Author(s): Keiko Ohgino, Kenzo Soejima, Daisuke Arai, Kota Ishioka, Takashi Sato, Hideki Terai, Shinnosuke Ikemura, Satoshi Yoda, Junko Hamamoto, Katsuhiko Naoki, Tomoko Betsuyaku
  • Organizer: AACR Annual Meeting 2012
  • Place of Presentation: USA (Chicago)
  • Year and Date: 2012-04-03
• [Presentation] Aberrant DNA methylation and expression of mRNA in EGFR-mutant lung cancer cell line with long-term gefitinib exposure (2011)
  • Author(s): Terai H, Soejima K, Naoki K, Satomi R, Nakayama S, Yoda S, Ikemura S, Sato T, Hamamoto J, Asano K, Betsuyaku T
  • Organizer: 第69回日本癌学会総会
  • Place of Presentation: 名古屋
• [Presentation] Aberrant DNA methylation and expression of mRNA in EGFR-mutant lung cancer cell line with long-term gefitinib exposure (2011)
  • Author(s): 寺井秀樹、猶木克彦、他
  • Organizer: 第69回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場、名古屋市、愛知県
• [Presentation] Expression of fibroblast growth factor-9 is associated with poor prognosis of resected non-small cell lung cancer patients.
  • Author(s): Keiko Ohgino, Kenzo Soejima, Daisuke Arai, Kota Ishioka, Takashi Sato, Hideki Terai, Shinnosuke Ikemura, Satoshi Yoda, Junko Hamamoto, Katsuhiko Naoki, Tomoko Betsuyaku.
  • Organizer: AACR Annual Meeting 2012
  • Place of Presentation: USA (Chicago)
• [Presentation] 長期ゲフィチニブ曝露によるEGFR変異肺癌細胞株におけるFGF2-FGFR1経路の活性化
  • 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、浜本純子、別役智子
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] EGFR-TKI耐性化後の再生検により扁平上皮癌と診断したNSCLC-NOSの2例
  • Author(s): 荒井大輔、黒田葵、谷哲夫、持丸貴生、扇野圭子、佐々木衛、石岡宏太、田中希宇人、安田浩之、石井誠、福永興壱、猶木克彦、田坂定智、副島研造、林雄一郎、別役智子
  • Organizer: 第166回日本肺癌学会関東支部会
  • Place of Presentation: 東京