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Basic and clinical study of EGFR gene mutation-positive lung cancer using a genetically modified mouse

Research Project

Project/Area Number 23390221
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionOkayama University

Principal Investigator

KIURA Katsuyuki  岡山大学, 大学病院, 教授 (10243502)

Co-Investigator(Kenkyū-buntansha) TKIGAWA Nagio  川崎医科大学, 医学部, 教授 (60325107)
HOTTA Katsuyuki  岡山大学, 大学病院, 講師 (70379816)
市原 英基  岡山大学, 医歯(薬)学総合研究科, 講師 (40549705)
Co-Investigator(Renkei-kenkyūsha) TAKATA Minoru  京都大学, 放射線生物研究センター, 教授 (30281728)
NAKABEPPU Yusaku  九州大, 学生体防御医学研究所, 教授 (30180350)
YOSHINO Tadashi  岡山大学, 医薬歯学総合研究科, 教授 (70183704)
Project Period (FY) 2011-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000)
Fiscal Year 2014: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2013: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2012: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2011: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
KeywordsEGFR遺伝子改変マウス / afatinib / everolimus (mTOR阻害薬), / JAK-1/2 inhibitors / cetuximab / bevacizumab / Ogg1ホモノックアウトマウス / NNK / EGFR / everolims / AZD1480 / gefitinib / 用量依存性 / 遺伝子改変マウス / mTOR阻害薬 / everolimus / JAK1/2阻害薬 / BIBW2552 / mTOR阻害薬
Outline of Final Research Achievements

① Using the EGFR genetically modified mice, afatinib (irreversible TKI), everolimus (mTOR inhibitor), and AZD1480 (JAK-1/2 inhibitors) revealed an anti-tumor effect. ②In mouse xenograft models, afatinib + cetuximab + bevacizumab combination therapy against resistant cells harbouring T790M has proved to result in lasting pathologic complete response. ③ Although 9.3% of Ogg1 (-/-) homozygous knockout mice to a high dose of tobacco-specific nitrosamines (NNK) had adenocarcinoma of the lung, it is not recognized carcinogenesis at low doses. The relationship between epidermal growth factor receptor (EGFR) gene mutations and NNK-induced carcinogenesis was unclear.

Report

(5 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • 2011 Annual Research Report

Research Products

(37 results)

All 2016 2015 2014 2013 2012 2011

All Journal Article Presentation Book

  • [Journal Article] Activation of EGFR baypass Signaling by TGFα Overexpression Induces Acquired Resistance to Alectinib in ALK-Translocated Lung Cancer Cells2016

    • Author(s)
      Sugiyama M., et al
    • Journal Title

      Mol Cancer Ther.

      Volume: 10 Pages: 1136-1146

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] A new human lung adenocarcinoma cell line harboring the EML4-ALK fusion gene.2014

    • Author(s)
      Isozaki H, Yasugi M, Takigawa N, Hotta K, Ichihara E, Taniguchi A, Toyooka S, Hashida S, Sendo T, Tanimoto M, Kiura K.
    • Journal Title

      Jpn J Clin Oncol

      Volume: 2014 Pages: 963-968

    • DOI
      10.1093/jjco/hyu110
    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer.2014

    • Author(s)
      Yasugi M, Takigawa N, Ochi N, Ohashi K, Harada D, Ninomiya T, Murakami T, Honda Y, Ichihara E, Tanimoto M, Kiura K.
    • Journal Title

      Exp Cell Res

      Volume: 326 Pages: 201-209

    • DOI
      10.1016/j.yexcr.2014.04.012
    • NAID
      120005526613
    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] The Role of STAT3 in Non-Small Cell Lung Cancer.2014

    • Author(s)
      Harada D, Takigawa N, Kiura K.
    • Journal Title

      Cancers (Basel)

      Volume: 6 Pages: 708-722

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer2014

    • Author(s)
      Ochi N, Takigawa N, Harada D, Yasugi M, Ichihara E, Hotta K, Tabata M, Tanimoto M, Kiura K.
    • Journal Title

      Experimental Cell Research

      Volume: 322 Pages: 168-177

    • DOI
      10.1016/j.yexcr.2014.01.007
    • NAID
      120005517858
    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Novel germ-line mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas2014

    • Author(s)
      Yamamoto H, Higasa K, Sakaguchi M, Shien K, Soh J, Ichimura K, Furukawa M, Hashida S, Tsukuda K, Takigawa N, Matsuo K, Kiura K, Miyoshi S, Matsuda F, Toyooka S.
    • Journal Title

      J Natl Cancer Inst.

      Volume: 106

    • DOI
      10.1093/jnci/djt338
    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency2013

    • Author(s)
      Takeda H, Takigawa N, Ohashi K, Minami D, Kataoka I, Ichihara E, Ochi N, Tanimoto M, Kiura K.
    • Journal Title

      Exp Cell Res.

      Volume: 319 Pages: 417-423

    • DOI
      10.1016/j.yexcr.2012.12.018
    • NAID
      120005359097
    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Afatinib prolongs survival compared to gefitinib in an epidermal growth factor receptor-driven lung cancer model2013

    • Author(s)
      Ninomiya T, Takigawa N, Ichihara E, Ochi N, Murakami T, Honda Y, Kubo T, Minami D, Kudo K, Tanimoto M, Kiura K.
    • Journal Title

      Molecular Cancer Therapeutics

      Volume: 12 Pages: 589-597

    • DOI
      10.1158/1535-7163.mct-12-0885
    • NAID
      120005359109
    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells2013

    • Author(s)
      Shien K, Toyooka S, Yamamoto H, Soh J, Jida M, Thu KL, Hashida S, Maki Y, Ichihara E, Asano H, Tsukuda K, Takigawa N, Kiura K, Gazdar AF, Lam WL, Miyoshi S.
    • Journal Title

      Cancer Res

      Volume: 73 Pages: 3051-3061

    • DOI
      10.1158/0008-5472.can-12-4136
    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Antitumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers.2013

    • Author(s)
      Saito K, Takigawa N, Ohtani N, Iioka H, Tomita Y, Ueda R, Fukuoka J, Kuwahara K, Ichihara E, Kiura K, Kondo E.
    • Journal Title

      Mol Cancer Ther.

      Volume: 12 Pages: 1-13

    • DOI
      10.1158/1535-7163.mct-12-1239
    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impact of physical size on gefitinib efficacy in patients with non-small cell lung cancer harboring EGFR mutations.2013

    • Author(s)
      Ichihara E, Hotta K, Takigawa N, Kudo K, Kato Y, Honda Y, Hayakawa H, Minami D, Sato A, Tabata M, Tanimoto M, Kiura K.
    • Journal Title

      Lung Cancer.

      Volume: 81 Pages: 435-439

    • DOI
      10.1016/j.lungcan.2013.05.021
    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lower gefitinib dose led to earlier resistance acquisition before emergence of T790M mutation in EGFR mutated lung cancer model.2013

    • Author(s)
      Hayakawa H, Ichihara E, Ohashi K, Ninomiya T, Yasugi M, Takata S, Sakai K, Matsumoto K, Takigawa N, Tanimoto M, Kiura K.
    • Journal Title

      Cancer Sci

      Volume: 104 Pages: 1440-1446

    • DOI
      10.1111/cas.12284
    • NAID
      120005468272
    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synergistic Elfect of Olaparib with Combination of Cisplatin on PTEN-Deficient Lung Cancer Cells.2013

    • Author(s)
      Takeda H, Takigawa N, Ohashi K, Minami D, Kataoka I, Ichihara E, Ochi N, Tanimoto M, Kiura K.
    • Journal Title

      Mol Cancer Res.

      Volume: 319 Pages: 417-423

    • DOI
      10.1158/1541-7786.mcr-12-0401
    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Subpopulation of small-cell lung cancer cells expressing CD133 and CD87 show resistance to chemotherapy.2013

    • Author(s)
      Kubo T, Takigawa N, Osawa M, Harada D, Ninomiya T, Ochi N, Ichihara E, Yamane H, Tanimoto M, Kiura K.
    • Journal Title

      Cancer Sci.

      Volume: 104 Pages: 78-84

    • DOI
      10.1111/cas.12045
    • NAID
      120005311967
    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1.2012

    • Author(s)
      Ohashi K, Sequist LV, Shien K, Aoe K, Toyooka S, Kiura K, Kris MG, Engelman JA, Vnencak-Jones CL, Dias-Santagata D, Ladanyi M, Pao W. et al
    • Journal Title

      Proc Natl Acad Sci U S A.

      Volume: 109

    • DOI
      10.1073/pnas.1203530109
    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Selective cyclooxygenase-2 inhibitor prevents cisplatin-induced tumorigenesis in A/J mice.2012

    • Author(s)
      Okada T, Takigawa N, Kishino D, Katayama H, Kuyama S, Sato K, Mimoto J, Ueoka H, Tanimoto M, Kiura K.
    • Journal Title

      Acta Med Okayama.

      Volume: 66 Pages: 1795-1802

    • NAID
      120004247096
    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation2012

    • Author(s)
      Harada D, Takigawa N, Ochi N, Ninomiya T, Yasugi M, Kubo T, Takeda H, Ichihara E, Ohashi K, Takata S, Tanimoto M, Kiura K
    • Journal Title

      Cancer Science

      Volume: 103 Pages: 1795-1802

    • DOI
      10.1111/j.1349-7006.2012.02363.x
    • NAID
      120005311974
    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] STAT3 expression in activating EGFR-driven adenocarcinoma of the lung2012

    • Author(s)
      Takata Saburo, Takigawa Nagio, Segawa Yoshihiko, Kubo Toshio, Ohashi Kadoaki, Kozuki Toshiyuki, Teramoto Norihiro, Yamashita Motohiro, Toyooka Shinichi, Tanimoto Mitsune, Kiura Katsuyuki
    • Journal Title

      Lung Cancer

      Volume: 75 Pages: 24-29

    • DOI
      10.1016/j.lungcan.2011.05.015
    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Establishment of pemetrexed-resistant non-small cell lung cancer cell lines2011

    • Author(s)
      Zhang D, Ochi N, Takigawa N, Tanimoto I, Ichihara E, Hotta K, Tabata M, Tanimoto M, Kiura K
    • Journal Title

      Cancer Lett

      Volume: 309 Pages: 228-235

    • DOI
      10.1016/j.canlet.2011.06.006
    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Presentation] Non-invasive EGFR T790M detection using droplet digital PCR system2015

    • Author(s)
      Shinsuke Hashida, Kadoaki Ohashi, Takehiro Matsubara, Tomoaki Ohtsuka, Mototsugu Watanabe1, Ken Suzawa1, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano1, Kazunori Tsukuda1, Shinichiro Miyoshi1, Katsuyuki Kiura1, Shinichi Toyooka1
    • Organizer
      The 106th Annual Meeting of the American Association for Cancer Research
    • Place of Presentation
      Philadelphia, PA, USA
    • Year and Date
      2015-04-22
    • Related Report
      2014 Annual Research Report
  • [Presentation] The impact of bevacizumab on combination low-dose afatinib and cetuximab therapy in lung cancer cells harboring activated EGFR mutations2015

    • Author(s)
      Kenichiro Kudo, Sr., Kadoaki Ohashi, Eiki Ichihara, Daisuke Minami, Hisao Kubo, Akiko Sato, Yuka Kato, Hideko Isozaki, Hiroe Kayatani, Tomoki Tamura, Mitsune Tanimoto, Katsuyuki Kiura.
    • Organizer
      The 106th Annual Meeting of the American Association for Cancer Research
    • Place of Presentation
      Philadelphia, PA, USA
    • Year and Date
      2015-04-20
    • Related Report
      2014 Annual Research Report
  • [Presentation] Both programmed cell death protein 1 and programmed death-ligand 1 molecules can be expressed on the cell surface of small-cell lung cancer2015

    • Author(s)
      Hiromichi Yamane1, Hideko Isozaki2, Nobuaki Ochi1, Kenichiro Kudo2, Yoshihiro Honda1, Tomoko Yamagishi1, Toshio Kubo2, Katsuyuki Kiura2, Nagio Takigawa1.Hiromichi Yamane1, Hideko Isozaki2, Nobuaki Ochi1, Kenichiro Kudo2, Yoshihiro Honda1, Tomoko Yamagishi1, Toshio Kubo2, Katsuyuki Kiura2, Nagio Takigawa1.
    • Organizer
      The 106th Annual Meeting of the American Association for Cancer Research
    • Place of Presentation
      Philadelphia, PA, USA
    • Year and Date
      2015-04-20
    • Related Report
      2014 Annual Research Report
  • [Presentation] Novel germline G660D mutation in HER2 gene detected by whole-exome sequencing can predispose a patient to developing familial lung adenocarcinoma2014

    • Author(s)
      Hiromasa Yamamoto, Koichiro Higasa, Masakiyo Sakaguchi, Kazuhiko Shien, Junichi Soh, Koichi Ichimura, Masashi Furukawa, Shinsuke Hashida, Kazunori Tsukuda, Nagio Takigawa, Keitaro Matsuo, Katsuyuki Kiura, Sinichiro Miyoshi, Fumihiko Matsuda, Shinichi Toyooka
    • Organizer
      The 105th Annual Meeting of the American Association for Cancer Research
    • Place of Presentation
      San Diego, CA. USA
    • Year and Date
      2014-04-09
    • Related Report
      2014 Annual Research Report
  • [Presentation] ALK inactivation induced acquired resistance to alectinib in lung cancer harboring EML4-ALK fusion gene.2014

    • Author(s)
      Hideko Isozaki, Eiki Ichihara, Masayuki Yasugi, Ocihi Nobuaki, Katsuyuki Hotta, Nagio Takigawa, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura
    • Organizer
      The 105th Annual Meeting of the American Association for Cancer Research
    • Place of Presentation
      San Diego, CA. USA
    • Year and Date
      2014-04-08
    • Related Report
      2014 Annual Research Report
  • [Presentation] Prognostic impact of cancer stem cell-related markers in non-small cell lung cancer patients treated with induction chemoradiotherapy2012

    • Author(s)
      Kazuhiko Shien, Shinichi Toyooka, Kouichi Ichimura, Junichi Soh, Takahiro Oto, Katsuyuki Kiura,
    • Organizer
      AACR Annual Meeting 2012
    • Place of Presentation
      McCormick Place in Chicago, Illinois
    • Related Report
      2012 Annual Research Report
  • [Presentation] Knockdown of EGFR to investigate its therapeutic potential for treatment of non-small cell lung cancers2012

    • Author(s)
      Junichi Soh, Kazuhiko Shien, Tsuyoshi Ueno, Norimitsu Tanaka, Hiromasa Yamamoto, Katsuyuki Kiura, Tetsuya Mitsudomi, Shinichi Toyooka, Shinichiro Miyoshi
    • Organizer
      AACR Annual Meeting 2012
    • Place of Presentation
      McCormick Place in Chicago, Illinois
    • Related Report
      2012 Annual Research Report
  • [Presentation] Afatinib prolonged survival in EGFR-driven lung cancer model compared to gefitinib2012

    • Author(s)
      Takashi Ninomiya, Eiki Ichihara, Akiko Hisamoto, Katsuyuki Hotta, Mitsune Tanimoto, Katsuyuki Kiura, Nagio Takigawa, Nobuaki Ochi, Masayuki Yasugi, Daijiro Harada.
    • Organizer
      AACR Annual Meeting 2012
    • Place of Presentation
      McCormick Place in Chicago, Illinois
    • Related Report
      2012 Annual Research Report
  • [Presentation] RAS signaling pathway gene mutations and acquired resistance to EGFR tyrosine-kinase inhibitors in EGFR mutant lung cancer2012

    • Author(s)
      Kadoaki Ohashi, Juliann Chmielecki, Ya-Lun Lin, Shinichi Toyooka, Katsuyuki Kiura, Roman Thomas, James Chih-Hsin Yang, Vincent Miller, Marc Ladanyi, Katerina Politi, William Pao1
    • Organizer
      AACR Annual Meeting 2012
    • Place of Presentation
      McCormick Place in Chicago, Illinois
    • Related Report
      2012 Annual Research Report
  • [Presentation] Effect of AZD1480 on lung tumor in transgenic mice carrying activating EGFR mutation2012

    • Author(s)
      Toshi Murakami, Nagio Takigawa, Takashi Ninomiya, Nobuhiro Honda, Hideko Isozaki, Eiki Ichihara, Akiko Hisamoto, Katsuyuki Hotta, Mitsune Tanimoto, Katsuyuki Kiura
    • Organizer
      AACR Annual Meeting 2012
    • Place of Presentation
      McCormick Place in Chicago, Illinois
    • Related Report
      2012 Annual Research Report
  • [Presentation] 肺がん治療の進歩2011

    • Author(s)
      木浦勝行
    • Organizer
      第45回日本内科学会近畿支部生涯教育講演会
    • Place of Presentation
      京都テルサ,京都
    • Year and Date
      2011-12-17
    • Related Report
      2011 Annual Research Report
  • [Presentation] Effect of afatinib on lung cancer burden induced by an exon 19 EGFR mutation in transgenic mice2011

    • Author(s)
      Ninomiya T, Takigawa N, Kubo T, Yasugi M, Honda Y, Minami D, Murakami T, Ichihara E, Tanimoto M, Kiura K
    • Organizer
      AACR Annual Meeting 2011
    • Place of Presentation
      Orange County Convention Center, Orlando, FL, USA
    • Year and Date
      2011-04-05
    • Related Report
      2011 Annual Research Report
  • [Presentation] Vascular endothelial growth factor receptor tyrosine kinase inhibitor inhibited mutated epidermal growth factor receptor-driven tumors ex vivo and in vivo2011

    • Author(s)
      Kubo T, Ohashi K, Osawa M, Takeda H, Ichihara E, Ninomiya T, Takigawa N, Harita S, Nakata Y, Tanimoto M, Kiura K
    • Organizer
      AACR Annual Meeting 2011
    • Place of Presentation
      Orange County Convention Center, Orlando, FL, USA
    • Year and Date
      2011-04-05
    • Related Report
      2011 Annual Research Report
  • [Presentation] JAK2/STAT3 induces erlotinib-resistance in lung cancer cells harboring EGFR-activating mutations2011

    • Author(s)
      Harada D, Takigawa N, Onashi K, Tchihara E, Toshio Kubo T, Takeda H, Kashihara H, Tanimoto M, Kiura K
    • Organizer
      AACR Annual Meeting 2011
    • Place of Presentation
      Orange County Convention Center, Orlando, FL, USA
    • Year and Date
      2011-04-03
    • Related Report
      2011 Annual Research Report
  • [Presentation] Role of ERK reactivation mediated by Src in acquired resistance to gefitinib in non-small cell lung cancer with EGFR mutation2011

    • Author(s)
      Ochi N, Takigawa N, Ohashi K, Takeda H, Fujii M, Kubo T, Ichihara E, Hotta K, Tanimoto M, Kiura K
    • Organizer
      AACR Annual Meeting 2011
    • Place of Presentation
      Orange County Convention Center, Orlando, FL, USA
    • Year and Date
      2011-04-03
    • Related Report
      2011 Annual Research Report
  • [Book] 【最新がん薬物療法学-がん薬物療法の最新知見-】 がん薬物治療薬の作用機序 分子標的治療薬 低分子化合物 ALK融合タンパク質チロシンリン酸化酵素阻害薬2014

    • Author(s)
      木浦勝行
    • Publisher
      日本臨床(0047-1852)72巻増刊2 最新がん薬物療法学
    • Related Report
      2014 Annual Research Report
  • [Book] Annual Review呼吸器2014 治療の進歩 EGFR-TKIs耐性肺癌に対する新しい分子標的治療2014

    • Author(s)
      木浦勝行
    • Publisher
      中外医学社
    • Related Report
      2014 Annual Research Report
  • [Book] 抗がん薬の臨床薬理Anti-cancer drugs and Pharmacology([監修]相羽惠介)1|受容体・シグナル伝達系阻害薬(小分子化合物) 1.HER阻害薬 2 Elrotinibを分担2013

    • Author(s)
      木浦勝行
    • Publisher
      南山堂
    • Related Report
      2013 Annual Research Report

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Published: 2011-04-06   Modified: 2019-07-29  

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