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

• Project/Area Number: 23390221
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Okayama 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: ¥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)
• Keywords: EGFR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.

Research Products

• [Journal Article] Activation of EGFR baypass Signaling by TGFα Overexpression Induces Acquired Resistance to Alectinib in ALK-Translocated Lung Cancer Cells (2016)
  • Author(s): Sugiyama M., et al
  • Journal Title: Mol Cancer Ther. Volume: 10 Pages: 1136-1146
  • 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
  • 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
  • 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
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer (2014)
  • 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
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel germ-line mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas (2014)
  • 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
  • Peer Reviewed
• [Journal Article] Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency (2013)
  • 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
  • Peer Reviewed
• [Journal Article] Afatinib prolongs survival compared to gefitinib in an epidermal growth factor receptor-driven lung cancer model (2013)
  • 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
  • Peer Reviewed
• [Journal Article] Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells (2013)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation (2012)
  • 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
  • Peer Reviewed
• [Journal Article] STAT3 expression in activating EGFR-driven adenocarcinoma of the lung (2012)
  • 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
  • Peer Reviewed
• [Journal Article] Establishment of pemetrexed-resistant non-small cell lung cancer cell lines (2011)
  • 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
  • Peer Reviewed
• [Presentation] Non-invasive EGFR T790M detection using droplet digital PCR system (2015)
  • 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
• [Presentation] The impact of bevacizumab on combination low-dose afatinib and cetuximab therapy in lung cancer cells harboring activated EGFR mutations (2015)
  • 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
• [Presentation] Both programmed cell death protein 1 and programmed death-ligand 1 molecules can be expressed on the cell surface of small-cell lung cancer (2015)
  • 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
• [Presentation] Novel germline G660D mutation in HER2 gene detected by whole-exome sequencing can predispose a patient to developing familial lung adenocarcinoma (2014)
  • 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
• [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
• [Presentation] Prognostic impact of cancer stem cell-related markers in non-small cell lung cancer patients treated with induction chemoradiotherapy (2012)
  • 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
• [Presentation] Knockdown of EGFR to investigate its therapeutic potential for treatment of non-small cell lung cancers (2012)
  • 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
• [Presentation] Afatinib prolonged survival in EGFR-driven lung cancer model compared to gefitinib (2012)
  • 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
• [Presentation] RAS signaling pathway gene mutations and acquired resistance to EGFR tyrosine-kinase inhibitors in EGFR mutant lung cancer (2012)
  • 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
• [Presentation] Effect of AZD1480 on lung tumor in transgenic mice carrying activating EGFR mutation (2012)
  • 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
• [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
• [Presentation] Effect of afatinib on lung cancer burden induced by an exon 19 EGFR mutation in transgenic mice (2011)
  • 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
• [Presentation] Vascular endothelial growth factor receptor tyrosine kinase inhibitor inhibited mutated epidermal growth factor receptor-driven tumors ex vivo and in vivo (2011)
  • 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
• [Presentation] JAK2/STAT3 induces erlotinib-resistance in lung cancer cells harboring EGFR-activating mutations (2011)
  • 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
• [Presentation] Role of ERK reactivation mediated by Src in acquired resistance to gefitinib in non-small cell lung cancer with EGFR mutation (2011)
  • 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
• [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
• [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
• [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