Molecular target therapy for multidrug-resistant small cell lung cancer

• Project/Area Number: 21590993
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Osaka University
• Principal Investigator: KIJIMA Takashi 大阪大学, 大学院・医学系研究科, 助教 (90372614)
• Research Collaborator: OTANI Yasushi 大阪大学, 医学部付属病院, 医員 ; MINAMI Toshiyuki 大阪大学, 大学院・医学系研究科, 院生
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 小細胞肺がん / 多剤耐性 / 分子標的治療 / CD9 / HER2 / 小細胞肺癌(SCLC) / ケモカイン / CXCR4 / ABCトランスポーター / ラパチニブ / 細胞接着誘導抗癌剤耐性(CAM-DR) / テトラスパニン / CXCL12

Research Abstract

Small cell lung cancer(SCLC) is highly malignant because it easily acquires multidrug resistance. We have found that CD9 and HER2 are upregulated on the cell surface of SCLC cells when they become multidrug-resistant. CD9 induced adhesion of SCLC cells to extracellular matrices(ECM) resulting in chemoresistance by augmenting anti-apoptotic signals via integrins. Inhibition of CD9 with blocking antibody or small interfering RNA induced apoptosis of chemoresistant SCLC cells. On the other hand, HER2 inhibitor lapatinib recovered the sensitivity of chemoresistant SCLC cells by inhibiting the function of drug-efflux pumps expressed on them. This inhibitory mechanism is found to include not only direct pump inhibition but also indirect mechanism through HER2 inactivation-mediated Src activation and caveolin-1 phosphorylation. These findings indicate the possibility of CD9 and HER2 as therapeutic target to overcome multidrug-resistance of SCLC.

Research Products

• [Journal Article] HER2 as therapeutic target for overcoming ATP-binding cassette transporter-mediated chemoresistance in small cell lung cancer (2012)
  • Author(s): 南俊行, 木島貴志, 大谷安司, 河面聡, 他
  • Journal Title: Molecular Cancer Therapeutics Volume: Vol.11(4) Pages: 830-841
  • Peer Reviewed
• [Journal Article] Cell surface tetraspanin CD9 mediates chemo-resistance in small cell lung cancer (2010)
  • Author(s): 河面聡, 木島貴志, 大谷安司, 南俊行, 他
  • Journal Title: Cancer Research Volume: Vol.70(20) Pages: 8025-8035
  • Peer Reviewed
• [Journal Article] Cell surface tetraspanin CD9 mediates chemoresistance in small cell lung cancer (2010)
  • Author(s): 河面聡, 木島貴志, 大谷安司, 南俊行, 他
  • Journal Title: Cancer Research Volume: VOL.70 Pages: 8025-8035
  • Peer Reviewed
• [Presentation] HER2陽性抗癌剤耐性小細胞肺癌におけるLapatinibのABCトランスポーター阻害効果 (2011)
  • Author(s): 南俊行, 木島貴志, 大谷安司, 河面聡, 他
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-05
• [Presentation] 小細胞肺癌の抗癌剤耐性におけるCD9の関与と治療標的としての可能性 (2009)
  • Author(s): 南俊行, 木島貴志, 大谷安司, 他
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-01
• [Presentation] 小細胞肺癌の抗癌剤耐性におけるCD9の関与と治療標的としての可能性 (2009)
  • Author(s): 大谷安司, 河面聡, 南俊行, 木島貴志, 他
  • Organizer: 第13回日本がん分子標的治療学会学術集会
  • Place of Presentation: 徳島
  • Year and Date: 2009-06-26
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/imed3/lab_8/index.html