不可逆性ＥＧＦＲ－ＴＫⅠとＥＧＦＲ抗体を用いたＥＧＦＲ－ＴＫⅠ耐性の克服

• 研究課題/領域番号: 24591184
• 研究種目: 基盤研究(C)
• 配分区分: 基金
• 応募区分: 一般
• 研究分野: 呼吸器内科学
• 研究機関: 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所)
• 研究代表者: 前門戸 任 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), がん先進治療開発研究部, 特任研究員 (40344676)
• 研究分担者: 田中 伸幸 地方独立法人宮城県立病院機構宮城県立がんセンター(研究所), がん先進治療開発研究部, 部長 (60280872)
• 研究期間 (年度): 2012-04-01 – 2015-03-31
• 研究課題ステータス: 完了 (2014年度)
• 配分額: 5,330千円 (直接経費: 4,100千円、間接経費: 1,230千円); 2014年度: 1,300千円 (直接経費: 1,000千円、間接経費: 300千円); 2013年度: 1,950千円 (直接経費: 1,500千円、間接経費: 450千円); 2012年度: 2,080千円 (直接経費: 1,600千円、間接経費: 480千円)
• キーワード: 癌 / 非小細胞肺癌 / 治療法 / 肺癌 / EGFR-TKI / EGFR

研究成果の概要

本研究では不可逆的EGFR-TKI＋EGFR抗体の２者併用によるEGFR-TKI耐性打破について解析した。EGFR-T790Mを発現するモデル細胞株に対して両者を併用したところ、Afatinib+Cetuximabが相乗効果を示した。シグナル伝達を解析したところ、アポトーシス関連分子であるBimが誘導されており、PARPとCaspas3の切断が起こっていた。EGFRの細胞内動態を調べたところ、Afatinib投与後によって細胞表面へのRab11依存性リサイクリングが増強していた。EGFRシグナル遮断によって細胞表面に増加したEGFRをEGFR抗体が認識し抗体依存性のEGFR分解を誘導していた。

研究成果

• [雑誌論文] Synergistic cytotoxicity of afatinib and cetuximab against EGFR T790M involves Rab11-dependent EGFR recycling. (2014)
  • 著者名/発表者名: Watanuki, Z.Kosai, H., Osanai, N., Ogama, N., Mochizuki, M., Tamai, K., Yamaguchi, K., Satoh, K., Fukuhara, T., Maemondo, M., Ichinose, M., Nukiwa, T., Tanaka, N.
  • 雑誌名: Biochem Biophy Res Commun 巻: 455 号: 3-4 ページ: 269-276
  • DOI: 10.1016/j.bbrc.2014.11.003
  • 査読あり / 謝辞記載あり
• [雑誌論文] Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. (2014)
  • 著者名/発表者名: Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, Yamamoto N, Hida T, Maemondo M, Nakagawa K, Nagase S, Okamoto I, Yamanaka T, Tajima K, Harada R, Fukuoka M, Yamamoto N.
  • 雑誌名: Lancet Oncol. 巻: 15 号: 11 ページ: 1236-1244
  • DOI: 10.1016/s1470-2045(14)70381-x
  • 査読あり
• [雑誌論文] An activation of LC3A-mediated autophagy contributes to de novo and acquired resistance to EGFR tyrosine kinase inhibitors in lung adenocarcinoma (2014)
  • 著者名/発表者名: Nihira K, Miki Y, Iida S, Narumi S, Ono K, Iwabuchi E, Ise K, Mori K, Saito M, Ebina M, Sato I, Maemondo M, Yamada-Okabe H, Kondo T, Sasano H. An activation of LC3A-mediated autophagy contributes to de novo and acquired resistance to EGFR tyrosine kinase inhibitors in lung adenocarcinoma.
  • 雑誌名: J Pathol 巻: 234 号: 2 ページ: 277-288
  • DOI: 10.1002/path.4354
  • 査読あり / 謝辞記載あり
• [雑誌論文] A phase II study of erlotinib monotherapy in pre-treated non-small cell lung cancer without EGFR gene mutation who have never/light smoking history: Re-evaluation of EGFR gene status (NEJ006/TCOG0903) (2014)
  • 著者名/発表者名: Matsumoto Y, Maemondo M, Ishii Y, Okudera K, Demura Y, Takamura K, Kobayashi K, Morikawa N, Gemma A, Ishimoto O, Usui K, Harada M, Miura S, Fujita Y, Sato I, Saijo Y;
  • 雑誌名: Lung Cancer 巻: 86 号: 2 ページ: 195-200
  • DOI: 10.1016/j.lungcan.2014.08.019
  • 査読あり / オープンアクセス
• [雑誌論文] Phase II study of amrubicin combined with carboplatin for refractory relapsed small-cell lung cancer: North Japan Lung Cancer Group Trial 0802 (2014)
  • 著者名/発表者名: Kawashima Y, Inoue A, Sugawara S, Oizumi S, Maemondo M, Okudera K, Suzuki T, Usui K, Harada M, Morikawa N, Hasegawa Y, Saito R, Ishimoto O, Sakakibara T, Asahina H, Nukiwa T.
  • 雑誌名: Respir Investig. 巻: 52 号: 3 ページ: 190-194
  • DOI: 10.1016/j.resinv.2013.12.005
  • 査読あり
• [雑誌論文] Randomized Phase II Trial Comparing Carboplatin Plus Weekly Paclitaxel and Docetaxel Alone in Elderly Patients With Advanced Non-Small Cell Lung Cancer: North Japan Lung Cancer Group Trial 0801 (2014)
  • 著者名/発表者名: Maemondo M, Inoue A, Sugawara S, Harada T, Minegishi Y, Usui K, Miwa K, Morikawa N, Kambe M, Ube K, Watanabe K, Ishimoto O, Sakakibara T, Gemma A, Nukiwa T
  • 雑誌名: Oncologist 巻: 19 号: 4 ページ: 352-353
  • DOI: 10.1634/theoncologist.2013-0411
  • 査読あり
• [雑誌論文] A prospective, phase II, open-label study (JO22903) of first-line erlotinib in Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC) (2013)
  • 著者名/発表者名: 3 ) Goto K, Nishio M, Yamamoto N, Chikamori K, Hida T, Maemondo M, Katakami N, Kozuki T, Yoshioka H, Seto T, Fukuyama T, Tamura T
  • 雑誌名: Lung Cancer 巻: vol.82 号: 1 ページ: 109-114
  • DOI: 10.1016/j.lungcan.2013.07.003
  • 査読あり
• [雑誌論文] Cigarette smoking and lung cancer risk according to histological type in Japanese men and women. (2013)
  • 著者名/発表者名: Seki T, Takahashi S, et al.
  • 雑誌名: Cancer Sci 巻: 104 号: 11 ページ: 1515-1522
  • DOI: 10.1111/cas.12273
  • 査読あり
• [雑誌論文] Updated Overall Survival Results from A Randomized Phase III Trial Comparing Gefitinib with Carboplatin-Paclitaxel for Chemo-Naive Non-Small Cell Lung Cancer with Sensitive EGFR Gene Mutations (NEJ002) (2013)
  • 著者名/発表者名: Inoue A, Kobayashi K, Maemondo M, et al
  • 雑誌名: Ann Oncol 巻: 24 号: 1 ページ: 54-9
  • DOI: 10.1093/annonc/mds214
  • 査読あり
• [雑誌論文] Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma (2012)
  • 著者名/発表者名: Inoue D, Suzuki T, Mitsuishi Y, Miki Y, Suzuki S, Sugawara S, Watanabe M, Sakurada A, Endo C, Uruno A, Sasano H, Nakagawa T, Satoh K, Tanaka N, Kubo H, Motohashi H, Yamamoto M
  • 雑誌名: Cancer Sci 巻: 103 号: 4 ページ: 760-766
  • DOI: 10.1111/j.1349-7006.2012.02216.x
  • 査読あり
• [雑誌論文] Quality of Life with Gefitinib in Patients with EGFR-Mutated Non-Small Cell Lung Cancer : Quality of Life Analysis of North East Japan Study Group 002 Trial (2012)
  • 著者名/発表者名: Oizumi S, Kobayashi K, Inoue A, Maemondo M, Sugawara S, Yoshizawa H, Isobe H, Harada M, Kinoshita I, Okinaga S, Kato T, Harada T, Gemma A, Saijo Y, Yokomizo Y, Morita S, Hagiwara K, Nukiwa T.
  • 雑誌名: Oncologist 巻: 17 号: 6 ページ: 863-70
  • DOI: 10.1634/theoncologist.2011-0426
  • 査読あり
• [雑誌論文] (2012)
  • 著者名/発表者名: Soda M, Isobe K, Inoue A, Maemondo M,Oizumi S, Fujita Y, Gemma A, Yamashita Y,Ueno T, Takeuchi K, Choi YL, Miyazawa H,Tanaka T, Hagiwara K, Mano H
  • 雑誌名: Clin Cancer Res 巻: 18 号: 20 ページ: 5682-5689
  • DOI: 10.1158/1078-0432.ccr-11-2947
  • 査読あり
• [雑誌論文] Runx1-deficiency in CD4+ T Cells Causes Fatal Autoimmune Inflammatory Lung Disease due to Spontaneous Hyperactivation of Cells (2012)
  • 著者名/発表者名: Wong WF
  • 雑誌名: J. Immunol. 巻: 188 号: 10 ページ: 5408-5420
  • DOI: 10.1038/bjc.2012.422
  • 査読あり
• [学会発表] Randomized phase 2 trial comparing amrubicin (A) with re-challenge of platinum doublet (P) in patients (pts) with sensitive-relapsed small-cell lung cancer (SCLC). (2014)
  • 著者名/発表者名: Atsushi Nakamura, Akira Inoue, Makoto Maemondo, Yoshiaki Mori, Satoshi Oizumi, Masao Harada, Shingo Takanashi, Naoto Morikawa, Takashi Ishida, Ichiro Kinoshita, Hiroshi Watanabe, Toshiro Suzuki, Taku Nakagawa, Ryota Saito, Toshihiro Nukiwa
  • 学会等名: 2014 ASCO annual meeting
  • 発表場所: Chicago, IL, USA
  • 年月日: 2014-05-30
• [学会発表] Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation–positive nonsquamous non-small cell lung cancer (NSCLC): An open-label randomized trial (2014)
  • 著者名/発表者名: Terufumi Kato, Takashi Seto, Makoto Nishio, Koichi Goto, Shinji Atagi, Yukio Hosomi, Noboru Yamamoto, Toyoaki Hida, Makoto Maemondo, Kazuhiko Nakagawa, Seisuke Nagase, Isamu Okamoto, Takeharu Yamanaka, Ryosuke Harada, Masahiro Fukuoka, Nobuyuki Yamamoto
  • 学会等名: 2014 ASCO annual meeting
  • 発表場所: Chicago, IL, USA
  • 年月日: 2014-05-30
• [学会発表] North East Japan Study Group/The Tokyo Cooperative Oncology Group; Randomized phase II study of concurrent gefitinib and chemotherapy versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer (NSCLC) with sensitive EGFR mutations: NEJ005/TCOG0902. (2014)
  • 著者名/発表者名: Satoshi Oizumi, Shunichi Sugawara, Koichi Minato, Toshiyuki Harada, Akira Inoue, Yuka Fujita, Makoto Maemondo, Hirohisa Yoshizawa, Kazuhiko Ito, Akihiko Gemma, Masaru Nishitsuji, Masao Harada, Hiroshi Isobe, Ichiro Kinoshita, Satoshi Morita, Kunihiko Kobayashi, Koichi Hagiwara, Minoru Kurihara, Toshihiro Nukiwa
  • 学会等名: 2014 ASCO annual meeting
  • 発表場所: Chicago, IL, USA
  • 年月日: 2014-05-30
• [学会発表] Randomized phase 2 study of carboplatin plus irinotecan (CI) versus carboplatin plus amrubicin (CA) for extensive disease small-cell lung cancer (ED-SCLC): NJLCG0901 (2014)
  • 著者名/発表者名: Yosuke Kawashima, Naoto Morikawa, Shunichi Sugawara, Makoto Maemondo, Toshiyuki Harada, Masao Harada, Akira Inoue, Yuka Fujita, Terufumi Kato, Hiroshi Yokouchi, Hiroshi Watanabe, Kazuhiro Usui, Toshiro Suzuki, Satoshi Oizumi, Hiroki Nagai, Mariko Kanbe, Toshihiro Nukiwa
  • 学会等名: 2014 ASCO annual meeting
  • 発表場所: Chicago, IL, USA
  • 年月日: 2014-05-30
• [学会発表] A Case of Small Cell Lung Cancer with Cancer-Associated Retinopathy (CAR) Accompanied by Circulating Anti-CRMP5/CV2 Antibodies (2013)
  • 著者名/発表者名: Mami Morita, Tatsuro Fukuhara, Yoko Tsukita, Zenta Watanuki, Aya Suzuki, Kana Watanabe, Nobuyuki Sato, Hidetoshi Takahashi, Shigemi Ito, Ikuro Sato, and Makoto Maemondo,
  • 学会等名: 18th Congress of the Asian Pacific Society of Respirology
  • 発表場所: 横浜市
• [学会発表] A phase I/II study with a highly selective ALK inhibitor CH5424802 in ALK-positive non-small cell lung cancer (NSCLC) patients: Updated safety and efficacy results from AF-001JP. J Clin Oncol 31, 2013 (suppl; abstr 8033) (2013)
  • 著者名/発表者名: Kazuhiko Nakagawa, Katsuyuki Kiura, Makoto Nishio, Takashi Seto, Makoto Maemondo, Akira Inoue, Toyoaki Hida, Nobuyuki Yamamoto, Hiroshige Yoshioka, Masao Harada, Yuichiro Ohe, Naoyuki Nogami, Kengo Takeuchi, Tadashi Shimada, Tomohiro Tanaka, Tomohide Tamura
  • 学会等名: 49th ASCO Annual Meeting
  • 発表場所: CHICAGO
• [学会発表] Phase II study of amrubicin (AMR) and carboplatin (CBDCA) for invasive thymoma (IT) and thymic carcinoma (TC): NJLCG0803. J Clin Oncol 31, 2013 (suppl; abstr 7530) (2013)
  • 著者名/発表者名: Yosuke Kawashima, Akira Inoue, Shunichi Sugawara, Masao Harada, Kunihiko Kobayashi, Toshiyuki Kozuki, Shoichi Kuyama, Tomohiro Sakakibara, Makoto Maemondo, Hajime Asahina, Akiko Hisamoto, Taku Nakagawa, Toshihiro Nukiwa
  • 学会等名: 49th ASCO Annual Meeting
  • 発表場所: CHICAGO
• [学会発表] Phase II study of combination therapy with S-1 and irinotecan in EGFR-mutated non-small cell lung cancer (NSCLC) resistant to both platinum-based chemotherapy and EGFR-TKI: NJLCG0804 (2013)
  • 著者名/発表者名: Maemondo M, Sugawara S, Harada T, Fukumoto S, Inoue A, Ishimoto O, Matsubara N, Harada M, Kobayashi K, Nukiwa T
  • 学会等名: The European Cancer Congress 2013
  • 発表場所: Amsterdam
• [学会発表] Phase II study of S-1 plus irinotecan for EGFR-mutated non-small cell lung cancer (NSCLC) resistant to both platinum-based chemotherapy and EGFR-TKI: NJLCG0804 (2013)
  • 著者名/発表者名: Akira Inoue, Shunichi Sugawara, Masao Harada, Makoto Maemondo, Toshiyuki Harada, Kunihiko Kobayashi, Osamu Ishimoto, Shinichi Fukumoto, Nobumichi Matsubara, Tetsuya Okano, Toshihiro Nukiwa
  • 学会等名: 15th World Conference on Lung Cancer
  • 発表場所: Sydney Australia
• [学会発表] North Japan Lung Cancer Group 0803 (2013)
  • 著者名/発表者名: Shoichi Kuyama, Akira Inoue, Masamoto Nakanishi, Yosuke Kawashima, Masao Harada, Kunihiko Kobayashi, Toshiyuki Kozuki, Tomohiro Sakakibara, Makoto Maemondo, Hajime Asahina, Akiko Hisamoto, Taku Nakagawa
  • 学会等名: 15th World Conference on Lung Cancer
  • 発表場所: Sydney Australia
• [学会発表] One-year follow-up of a Phase I/II study of a highly selective ALK inhibitor CH5424802/RO5424802 in ALK-rearranged advanced non-small cell lung cancer (NSCLC) North Japan Lung Cancer Group 0803 (2013)
  • 著者名/発表者名: Akira Inoue, Makoto Nishio, Katsuyuki Kiura, Takashi Seto, Kazuhiko Nakagawa, Makoto Maemondo, Toyoaki Hida, Hiroshige Yoshioka, Masao Harada, Yuichiro Ohe, Naoyuki Nogami, Haruyasu Murakami, Kengo Takeuchi, Kazue Kikuchi, Takashi Asakawa, Shumpei Yokoyama, Tomohide Tamura
  • 学会等名: 15th World Conference on Lung Cancer
  • 発表場所: Sydney Australia
• [学会発表] Variability of epidermal growth factor receptor (EGFR) mutations in serum during erlotinib therapy and its clinical implications: exploratory analysis of a phase II study of erlotinib in patients with advanced non-small-cell lung cancer (NSCLC) harboring (2013)
  • 著者名/発表者名: Makoto Maemondo, Makoto Nishio, Noboru Yamamoto, Kenichi Chikamori, Nobuyuki Katakami, Toyoaki Hida, Takashi Seto, Hiroshige Yoshioka, Toshiyuki Kozuki, Norihisa Ohishi, Tomohide Tamura
  • 学会等名: 15th World Conference on Lung Cancer
  • 発表場所: Sydney Australia
• [学会発表] A phase ll study of erlotinib monotherpay in previously treated advanced non-small cell lung cancer(NSCLC) without EGFR gene mutation who have never/light smoking history (2012)
  • 著者名/発表者名: Maemondo M
  • 学会等名: ESMO
  • 発表場所: Australia
• [学会発表] Final analysis of randomized phase ll trial of carboplatin combined with weekly paclitaxel(CP) and docetaxel alone(D) in elderly patients(pts) with advanced non-small cell lung cancer(NSCLC): (2012)
  • 著者名/発表者名: Maemondo M
  • 学会等名: ESMO
  • 発表場所: Australia
• [図書] ガイドラインには載っていない肺がん Practical Treatment, “EGFR野生型” 肺がんに対するEGFR-TKI治療 (2014)
  • 著者名/発表者名: 前門戸任
  • 出版者: MEDICAL VIEW社
• [図書] Medical Practice M.P, vol.30/No.7 One Point Advice, Do not harm (2013)
  • 著者名/発表者名: 前門戸任
  • 総ページ数: 268
  • 出版者: 文光堂