Novel molecular mechanisms of acquired resistance to gefitinib in lung adenocarcinoma

• Project/Area Number: 25830111
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Kanazawa University
• Principal Investigator: NAKATA Asuka 金沢大学, がん進展制御研究所, 助教 (70597921)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肺腺癌 / イレッサ / 肺癌 / イレッサ耐性 / 肺がん / gefitinib / EGFR-TKI

Outline of Final Research Achievements

Although Iressa (gefitinib) were greatly effective in lung adenocarcinoma patients harboring EGFR mutations, these patients ultimately have acquired resistance to gefitinib. To explore novel molecular mechanisms for gefitinib-resistance, we established the gefitinib-resistant PC9M2 cells that were spontaneously derived from gefitinib-sensitive PC9. Microarray analysis revealed that β－catenin-related genes were upregulated in PC9M2 cells compared with PC9 cells. We next demonstrated that the downregulation of β-catenin partially restored the sensitivity to gefitinib in PC9M2 cells. Using the tissues from lung cancer patients harbored EGFR mutation, we showed that activation of β-catenin was related with gefitinib sensitivity in patient’s samples, suggesting that enhanced β-catenin activation is associated with primary and acquired resistance to gefitinib. Targeting β-catenin pathway may be useful for overcoming the resistance to gefitinib

Research Products

• [Journal Article] A comparative study of statistical methods used to identify dependencies between gene expression signals. (2014)
  • Author(s): S.S. Santos, D. Y. Takahashi, A. Nakata, A. Fujita
  • Journal Title: Briefings in bioinformatics Volume: 15 Issue: 6 Pages: 906-18
  • DOI: 10.1093/bib/bbt051
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Novel molecular mechanisms of acquired resistance to gefitinib in lung adenocarcinoma (2014)
  • Author(s): 中田飛鳥,吉田亮, 山口類 ,山内麻衣,玉田嘉紀,藤田アンドレ, 島村徹平,井元清哉,樋口知之, 野村将春, 矢野聖二,宮野悟,後藤典子
  • Organizer: 4th FUSCC-CRIKU Joint Symposium on Tumor Biology
  • Place of Presentation: 上海 （中国）
  • Year and Date: 2014-10-14
• [Presentation] 早期肺癌における遺伝子発現シグネチャーによる予後予測診断システムの開発 (2014)
  • Author(s): 中田飛鳥,藤田アンドレ, Guoan Chen, 河野隆志, 東條有伸, David G. Beer, 後藤典子
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 早期肺癌における遺伝子発現シグネチャーによる予後予測診断システムの開発 (2014)
  • Author(s): 中田飛鳥,藤田アンドレ, Guoan Chen, 河野隆志, 東條有伸, David G. Beer, 後藤典子
  • Organizer: 第34回日本分子腫瘍マーカー研究会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-24
• [Presentation] Novel molecular mechanisms of acquired resistance to gefitinib in lung adenocarcinoma (2014)
  • Author(s): 中田 飛鳥
  • Organizer: Keystone Symposia Developmental Pathways and Cancer: Wnt, Notch and Hedgehog
  • Place of Presentation: バンフ（カナダ）
• [Presentation] Novel molecular mechanisms of acquired resistance to gefitinib in Non-small lung cancer (2013)
  • Author(s): 中田 飛鳥
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜