不可逆性ＥＧＦＲ－ＴＫⅠとＥＧＦＲ抗体を用いたＥＧＦＲ－ＴＫⅠ耐性の克服

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24591184
• Research Institution: Miyagi Prefectural Hospital Organization Miyagi Cancer Center
• Principal Investigator: 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)
• Co-Investigator(Kenkyū-buntansha): 田中 伸幸 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, 部長 (60280872)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 癌 / 肺癌 / EGFR-TKI

Outline of Annual Research Achievements

EGFR遺伝子変異陽性肺癌に対するヒト上皮増殖因子チロシンキナーゼ阻害剤（EGFR－TKI）治療は、従来の化学療法より明らかに優れた治療であるが、耐性獲得が問題であった。耐性を克服する方策として、不可逆的EGFR-TKI＋EGFR抗体の２者併用が有効であるが、耐性克服の機序はほぼ未解明のままである。本課題では、耐性克服がなぜ可能となるのか？という問いに答えるため、細胞レベルと個体レベルで治療モデルを構築し、細胞生物学的に原因を探る。本年度はEGFR-TKIと抗EGFR抗体であるCetuximabを併用し治療効果を検討した。昨年度構築した細胞株のうちGefitinib耐性かつAfatinib部分感受性の株であるK56-EGFR-T790M変異体系に対して両者を併用した。その結果、Afatinib+Cetuximabが相乗効果を示した。細胞死を検討したところ、Proapoptotic分子であるBimが誘導されており、PARPおよびCaspas3の切断が起こっていた。Afatinib投与後の細胞表面EGFRをFACS法により検討したところ、細胞表面へのリサイクルが増強していた。この作用はリサイクリング関連分子Rab11によって起こることが判明した。したがって、Afatinibによって細胞表面に増加したEGFRをCetuximabが効果的に認識し抗体依存性のEGFR分解を誘導することがわかった。以上の研究成果は新たなT790M変異陽性の非小細胞肺癌に有効であると考えられ、今後の実臨床への応用が期待される。

Research Products

• [Journal Article] Synergistic cytotoxicity of Afatinib and Cetuximab against EGFR T790M involves Rab11-dependent EGFR recycling (2014)
  • Author(s): Watanuki Z, Kosai H, Osanai N, Ogama N, Mochizuki M, Tamai K, Yamaguchi K, Satoh K, Fukuhara T, Maemondo M, Ichinose M, Nukiwa T, Nobuyuki Tanaka
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 455 Pages: 269-276
  • DOI: 10.1016/j.bbrc.2014.11.003
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 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)
  • Author(s): 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.
  • Journal Title: Lancet Oncol. Volume: 15 Pages: 1236–1244
  • DOI: 10.1016/S1470-2045(14)70381-X
  • Peer Reviewed
• [Journal Article] An activation of LC3A-mediated autophagy contributes to de novo and acquired resistance to EGFR tyrosine kinase inhibitors in lung adenocarcinoma (2014)
  • Author(s): 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.
  • Journal Title: J Pathol Volume: 234 Pages: 277-288
  • DOI: 10.1002/path.4354
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 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)
  • Author(s): 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;
  • Journal Title: Lung Cancer Volume: 86 Pages: 195-200
  • DOI: 10.1016/j.lungcan.2014.08.019
  • Peer Reviewed
• [Journal Article] Phase II study of amrubicin combined with carboplatin for refractory relapsed small-cell lung cancer: North Japan Lung Cancer Group Trial 0802 (2014)
  • Author(s): 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.
  • Journal Title: Respir Investig. Volume: 52 Pages: 190-194
  • DOI: 10.1016/j.resinv.2013.12.005
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: Oncologist Volume: 19 Pages: 352-353
  • DOI: 10.1634/theoncologist.2013-0411
  • Peer Reviewed
• [Presentation] 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)
  • Author(s): 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
  • Organizer: 2014 ASCO annual meeting
  • Place of Presentation: Chicago, IL, USA
  • Year and Date: 2014-05-30
• [Presentation] 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)
  • Author(s): 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
  • Organizer: 2014 ASCO annual meeting
  • Place of Presentation: Chicago, IL, USA
  • Year and Date: 2014-05-30
• [Presentation] 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)
  • Author(s): 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
  • Organizer: 2014 ASCO annual meeting
  • Place of Presentation: Chicago, IL, USA
  • Year and Date: 2014-05-30
• [Presentation] 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)
  • Author(s): 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
  • Organizer: 2014 ASCO annual meeting
  • Place of Presentation: Chicago, IL, USA
  • Year and Date: 2014-05-30