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Antitumor effects of monoclonal antibodies affecting dimerization between ErbB family members

Research Project

Project/Area Number 18590088
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionSetsunan University

Principal Investigator

ITO Fumiaki  Setsunan University, DEPARTMENT OF BIOCHEMISTRY, PROFESSOR (80111764)

Co-Investigator(Kenkyū-buntansha) NISHIO Kazuto  KINKI UNVERSITY, SCHOOL OF MEDICINE, DEPARTMENT OF GENOME BIOLOGY, PROFESSOR (10208134)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsEGF receptor / Monoclonal antibody therapy / Anti-cancer drugs / Tyrosine kinase inhibitors / Molecular targeting drugs / ErbB2 / ErbB3 / Non-small lung cancer / 抗がん剤 / 非小細胞肺がん / イレッサ / EGF受容体の二量体化
Research Abstract

Epidermal growth factor receptor (EGFR) forms homodimers and heterodimers with the other ErbB family members, ErbB2, ErbB3, and ErbB4. ErbB family members play fundamental roles in cell growth and cell survival, and they are targets for monoclonal antibody (mAb) therapy of cancer, because inappropriate ErbB activity has been implicated in several human cancer cells. However, our understanding of the pharmacological effects of mAb on tumor growth is not well developed. In this study, we examined effects of our mAb against EGFR, designated as B4G7, on growth of human non-small cell lung cancer cell lines (PC-9, PC14, and A549) as well as on that of A431 human epidermoid carcinoma cells. B4G7, but not EGF, exhibited growth-stimulatory effect upon all of these human cancer cell lines. The B4G7-stimulated cell growth was not affected by AG1478, a specific inhibitor of EGFR tyrosine kinase. Thus, the growth stimulation by B4G7 appears to be independent of the activation of EGFR tyrosine kinase. Immunoprecipitation with anti-ErbB3 antibody revealed that B4G7, but not EGF, stimulated heterodimerization between ErbB2 and ErbB3. ErbB3 was tyrosine-phosphorylated in the presence of B4G7 but not in the presence of EGF. Further, the phosphorylation of ErbB3 and B4G7-induced increase in cell growth were inhibited by AG825, a specific inhibitor of ErbB2, indicating that the ErbB2/ErbB3 dimer functions to promote cell growth in B4G7-treated cells. These findings show that ErbB family members other than EGFR affect sensitivity to EGFR-directed antibody therapies for cancer. Examination of expression levels of ErbB2 and ErbB3 in cancer cells is of importance in optimizing EGFR family-directed therapies for cancer.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (25 results)

All 2008 2007 2006 Other

All Journal Article (4 results) (of which Peer Reviewed: 1 results) Presentation (19 results) Remarks (2 results)

  • [Journal Article] Growth stimulation of non-small cell lung cancer cell lines by antibody against epidermal growth factor receptor promoting formation of ErbB2/ErbB3 heterodimers2007

    • Author(s)
      Mari Maegawa, Fumiaki Ito, 他5名
    • Journal Title

      Mol Cancer Res 5(4)

      Pages: 393-401

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] 「研究成果報告書概要(欧文)」より2007

    • Author(s)
      Mari Maegawa, Kenji Takeuchi, Eishi Funakoshi, Katsumi Kawasaki, Kazuto Nishio, Nobuyoshi Shimizu, Fumiaki Ito
    • Journal Title

      Mol Cancer Res 5-4

      Pages: 393-401

    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Growth stimulation of Non-small Cell Lung Cancer Cell Lines by Antibody against EGF Receptor Promoting Formation of ErbB2/ErbB3 Heterodimers2007

    • Author(s)
      M.Maegawa, K.Takeuchi, E.Funakoshi, K.Kawasaki, K.Nishio, N.Shimizu, F.Ito
    • Journal Title

      Molecular Cancer Research 5(4)

      Pages: 393-401

    • Related Report
      2006 Annual Research Report
  • [Journal Article] 「研究成果報告書概要(欧文)」より2006

    • Author(s)
      Kenji Takeuchi, Yu-ichiro Motoda, Fumiaki Ito
    • Journal Title

      FEBS Journal 273

      Pages: 3743-3755

    • Related Report
      2007 Final Research Report Summary
  • [Presentation] EGF受容体チロシンキナーゼ阻害剤に対する耐性獲得機構の解析2008

    • Author(s)
      新屋 智寛
    • Organizer
      日本薬学会第128年会
    • Place of Presentation
      横浜
    • Year and Date
      2008-03-27
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] ミトコンドリア経路を介したアポトーシスに対するインスリンの抑制作用2008

    • Author(s)
      竹内 健治
    • Organizer
      日本薬学会第128年会
    • Place of Presentation
      横浜
    • Year and Date
      2008-03-27
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor2008

    • Author(s)
      Tomohiro Shinya, Mari Maegawa, Kazuto Nishio, Fumiaki Ito
    • Organizer
      128th Annual Meeting of the Pharmaceutical Society of Japan
    • Place of Presentation
      Yokohama
    • Year and Date
      2008-03-27
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Insulin prevents apoptosis induced by a specific inhibitor of EGFR kinase but not by adriamycin2008

    • Author(s)
      Yu-suke Nakao, Kenji Takeuchi, Fumiaki Ito
    • Organizer
      128th Annual Meeting of the Pharmaceutical Society of Japan
    • Place of Presentation
      tyrosine Yokohama
    • Year and Date
      2008-03-27
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 上皮増殖因子(EGF)によるBcl-2ファミリータンパク質を標的としたアポトーシス抑制機構の解析2007

    • Author(s)
      竹内 健治
    • Organizer
      BMB 2007
    • Place of Presentation
      横浜
    • Year and Date
      2007-12-12
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Bc1-2 family members as a target for the protective action of epidermal growth factor against adriamycin-induced apoptosis2007

    • Author(s)
      Kenji Takeuchi, Yuuki Sato, Fumiaki Ito
    • Organizer
      BMB2007
    • Place of Presentation
      Yokohama
    • Year and Date
      2007-12-12
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 上皮増殖因子(EGF)によるBcl-2ファミリータンパク質を標的としたアポトーシス抑制機構の解析2007

    • Author(s)
      竹内 健治
    • Organizer
      BMB2007
    • Place of Presentation
      横浜
    • Year and Date
      2007-12-12
    • Related Report
      2007 Annual Research Report
  • [Presentation] インスリンによるEGF受容体チロシンキナーゼ阻害剤耐性獲得機構の解析2007

    • Author(s)
      伊藤 文昭
    • Organizer
      第66回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2007-10-05
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] 変異型EGFRのシグナル伝達経路2007

    • Author(s)
      前川 麻里
    • Organizer
      第66回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2007-10-05
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Protective action of insulin against EGFR tyrosine kinase inhibitor AG1478-induced apoptosis2007

    • Author(s)
      Fumiaki Ito, Yoshimasa Matsuda, Kazuto Nishio, Kenji Takeuchi
    • Organizer
      66th Annual Meeting of the Japanese Cancer Association
    • Place of Presentation
      Yokohama
    • Year and Date
      2007-10-05
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] A novel signaling pathway of deletional mutant EGFR2007

    • Author(s)
      Mari Maegawa, HideyukiYokote, Kazuko Matsumoto, Kaoru Tanaka, Hiroyasu Kaneda, Yoshihiko Fujita, Marco De Verasco, Tokuzo Arao, Fumiaki Koizumi, Fumiaki Ito, Kazuto Nishio
    • Organizer
      66th Annual Meeting of the Japanese Cancer Association
    • Place of Presentation
      Yokohama
    • Year and Date
      2007-10-05
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] EGF受容体チロシンキナーゼ阻害剤が誘導するアポトーシスに対するインスリンの抑制作用2006

    • Author(s)
      松田 吉正
    • Organizer
      MBSJ Forum 2006
    • Place of Presentation
      京都
    • Year and Date
      2006-12-08
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 抗EGF受容体抗体のヒト非小細胞肺がん株の増殖とシグナル伝達に与える影響2006

    • Author(s)
      伊藤 文昭
    • Organizer
      第65回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2006-09-29
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Effects of ant-EGFR antibody on growth and downstream signaling of human non-small-cell lung cancer cell lines2006

    • Author(s)
      Fumiaki Ito, Mari Maegawa, Kazuto Nishio, Nobuyoshi Shimizu
    • Organizer
      65th Annual Meeting of the Japanese Cancer Association
    • Place of Presentation
      Yokohama
    • Year and Date
      2006-09-29
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Protective action of insulin against apoptosis induced by EGFR tyrosine kinase inhibitor2006

    • Author(s)
      Yoshimasa Matsuda, Kazufurni Uchida, Yukari Inoue, Kenji Takeuchi, Kazuto Nishio, Fumiaki Ito
    • Organizer
      MBSJ Forum 2006
    • Place of Presentation
      Kyoto
    • Year and Date
      2006-09-08
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Growth-stimulatory effect of anti-EGF receptor antibody upon two non-small lung cancer cell lines2006

    • Author(s)
      伊藤 文昭
    • Organizer
      20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress
    • Place of Presentation
      京都
    • Year and Date
      2006-06-21
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Role of transcription factor AP1 in epidermal growth factor(EGF)-mediated protection against apoptosis induced by a DNA-damaging agent2006

    • Author(s)
      竹内 健治
    • Organizer
      20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress
    • Place of Presentation
      京都
    • Year and Date
      2006-06-21
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Growth-stimulatory effect of anti-EGF receptor antibody upon two non-small lung cancer cell lines2006

    • Author(s)
      Fumiaki Ito, Mari Maegawa, Kazuto Nishio, Nobuyoshi Shimizu
    • Organizer
      20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress
    • Place of Presentation
      Kyoto
    • Year and Date
      2006-06-21
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Role of transcription factor AP1 in epidermal growth factor(EGF)-mediated protection against apoptosis induced by a DNA-damaging agent2006

    • Author(s)
      Kenji Takeuchi, Yu-ichiro Motoda, Fumiaki Ito
    • Organizer
      20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress
    • Place of Presentation
      Kyoto
    • Year and Date
      2006-06-21
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Remarks] 「研究成果報告書概要(和文)」より

    • URL

      http://www.setsunan.ac.jp/~p-seika/gyouseki..htm

    • Related Report
      2007 Final Research Report Summary
  • [Remarks]

    • URL

      http://www.setsunan.ac.jp/~p-seika/gyouseki.htm

    • Related Report
      2007 Annual Research Report

URL: 

Published: 2006-04-01   Modified: 2016-04-21  

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