遺伝子改変マウスを利用したＥＧＦＲ遺伝子変異陽性肺癌の基礎的臨床的検討

2014 Fiscal Year Annual Research Report

• Project/Area Number: 23390221
• Research Institution: Okayama University
• Principal Investigator: 木浦 勝行 岡山大学, 大学病院, 教授 (10243502)
• Co-Investigator(Kenkyū-buntansha): 瀧川 奈義夫 川崎医科大学, 医学部, 教授 (60325107) ; 堀田 勝幸 岡山大学, 大学病院, 助教 (70379816)
• Project Period (FY): 2011-04-01 – 2015-03-31
• Keywords: EGFR / EGFR遺伝子改変マウス / afatinib / everolims / AZD1480 / gefitinib / bevacizumab / 用量依存性

Outline of Annual Research Achievements

pEGFR/pHER2/HER4のリン酸化を不可逆的に抑制出来るafatinibはT790M変異を有するgefitinib耐性株に対してもより強い増殖抑制効果を示し，EGFR遺伝子改変マウス(mouse Egfr del E748-A752, EGFR delE746-A75 ）のgefitinibと比較して全生存期間を有意に延長することを証明した。マウス異種移植モデルでVEGF-Aに対する抗体bevacizumabとafatinibを併用することで，T790Mを有する耐性細胞に対して優れた抗腫瘍効果を示すことを証明し,afatinib単剤あるいはbevacizumab併用での臨床応用の可能性を示した。更にこれらを発展させて研究でL858RT790Mを有するH1975,exon19 del T790Mを有するRPC-9のGatekeeper mutation を有するEGFRTKI耐性細胞に対して, afatinib + cetuximab + bevacizumab併用療法をマウス異種移植モデルで検討すると，有害事象を増加させることなく，１ヵ月後には病理学的完全奏効，治療をoffにしてもその効果は１ヶ月以上続くことを発見した。
mTOR阻害薬であるeverolimus連日経口投与によりヒトEGFR L858R遺伝子導入マウスの生存期間を無治療群と比較して有意に延長した。JAK1/2阻害薬であるAZD1480はマウスEgfr遺伝子改変マウスの生存期間を無治療群と比較して有意に延長した。EverolimusもAZD1780も試験管内の実験であるがgefitinib耐性細胞RPC-9細胞株に感受性を残していた。これらの結果は，EGFR遺伝子変異陽性肺癌に対するafatinib, everolimus，AZD1480 afatinib + cetuximab + bevacizumab併用療法の臨床応用の可能性を示している。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [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] Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors. (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.
  • 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
  • DOI: .10.3390/cancers6020709.
  • 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: Exp Cell Res Volume: 6 Pages: 201-209
  • DOI: 10.1016/j.yexcr.2014.04.012.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model. (2014)
  • Author(s): Murakami T, Takigawa N, Ninomiya T, Ochi N, Yasugi M, Honda Y, Kubo T, Ichihara E, Hotta K, Tanimoto M, Kiura K.
  • Journal Title: Lung Cancer Volume: 322 Pages: 30-36
  • DOI: 10.1016/j.yexcr.2014.01.007.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel germline 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 Pages: djt338.
  • DOI: 10.1093/jnci/djt338.
  • 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 – 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 – 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 – 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 – 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 – 2014-04-08
• [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
  • Total Pages: 704,Page182-187(2014.02)
  • 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
  • Total Pages: 273, Page196-206(2014.01)
  • Publisher: 中外医学社