不可逆性ＥＧＦＲ－ＴＫIとＥＧＦＲ抗体を用いたＥＧＦＲ－ＴＫI耐性の克服

2013 Fiscal Year Research-status Report

• Project/Area Number: 24591184
• Research Institution: 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)
• 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)
• Keywords: 癌 / 肺癌 / EGFR-TKI

Research Abstract

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、細胞レベルおよび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。本年度は野生型及び遺伝子変異型EGFR発現細胞系の構築とEGFRタンパク発現安定性の解析を行った。培養細胞株としてEGFRの内因性発現が最少である細胞をスクリーニングしたところK562が最適であることが判明した。そこで、EGFR（野生型、変異型及びEGFR-TKI耐性獲得型）の発現ベクターを作成し、各種EGFR発現系を構築した。レトロウイルスベクターにヒトEGFR遺伝子として、野生型,Exon19del, L858R, Exon19del/T790M, L858R/T790M を導入した。各種EGFR安定発現細胞株に対し、Imatinib存在条件においてGefitinib, Erlotinib, Afatinibによる細胞死を解析した。その結果、GefitinibとErlotinibは野生型のほかExon19del, L858Rに奏効した。一方、L858R/T790MはAfatinibのみ効果があった。一方、抗EGFR抗体であるCetuximabはすべてのEGFRに部分的にしか奏効しなかった。以上の結果から、EGFR-TKIの効果を解析する良い実験系として機能することが確かめられた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

薬剤の効果が実臨床と一致する結果であるなど、有力な評価系の構築に成功した。予定通り順調である。

Strategy for Future Research Activity

当初予定通りに薬剤相乗効果、細胞死のメカニズムなどを継続して解析する予定である。

Expenditure Plans for the Next FY Research Funding

薬剤評価系が予想以上に順調に樹立できたため。
試薬、抗体等に充当し当初目的の完遂に利用する。

Research Products

• [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
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: Lung Cancer Volume: vol.82 Pages: 109-114
  • DOI: 10.1016/j.lungcan.2013.07.003
  • Peer Reviewed
• [Journal Article] Cigarette smoking and lung cancer risk according to histologic type in Japanese men and women (2013)
  • Author(s): 4 ) Seki T, Nishino Y, Tanji F, Maemondo M, Takahashi S, Sato I, Kawai M, Minami Y.
  • Journal Title: Cancer Sci Volume: vol.104 Pages: 1515-1522
  • DOI: 10.1111/cas.12273
  • Peer Reviewed
• [Presentation] A Case of Small Cell Lung Cancer with Cancer-Associated Retinopathy (CAR) Accompanied by Circulating Anti-CRMP5/CV2 Antibodies (2013)
  • Author(s): Mami Morita, Tatsuro Fukuhara, Yoko Tsukita, Zenta Watanuki, Aya Suzuki, Kana Watanabe, Nobuyuki Sato, Hidetoshi Takahashi, Shigemi Ito, Ikuro Sato, and Makoto Maemondo,
  • Organizer: 18th Congress of the Asian Pacific Society of Respirology
  • Place of Presentation: 横浜市
  • Year and Date: 20131114-20131114
• [Presentation] 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)
  • Author(s): Akira Inoue, Shunichi Sugawara, Masao Harada, Makoto Maemondo, Toshiyuki Harada, Kunihiko Kobayashi, Osamu Ishimoto, Shinichi Fukumoto, Nobumichi Matsubara, Tetsuya Okano, Toshihiro Nukiwa
  • Organizer: 15th World Conference on Lung Cancer
  • Place of Presentation: Sydney Australia
  • Year and Date: 20131027-20131030
• [Presentation] North Japan Lung Cancer Group 0803 (2013)
  • Author(s): Shoichi Kuyama, Akira Inoue, Masamoto Nakanishi, Yosuke Kawashima, Masao Harada, Kunihiko Kobayashi, Toshiyuki Kozuki, Tomohiro Sakakibara, Makoto Maemondo, Hajime Asahina, Akiko Hisamoto, Taku Nakagawa
  • Organizer: 15th World Conference on Lung Cancer
  • Place of Presentation: Sydney Australia
  • Year and Date: 20131027-20131030
• [Presentation] 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)
  • Author(s): 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
  • Organizer: 15th World Conference on Lung Cancer
  • Place of Presentation: Sydney Australia
  • Year and Date: 20131027-20131030
• [Presentation] 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)
  • Author(s): Makoto Maemondo, Makoto Nishio, Noboru Yamamoto, Kenichi Chikamori, Nobuyuki Katakami, Toyoaki Hida, Takashi Seto, Hiroshige Yoshioka, Toshiyuki Kozuki, Norihisa Ohishi, Tomohide Tamura
  • Organizer: 15th World Conference on Lung Cancer
  • Place of Presentation: Sydney Australia
  • Year and Date: 20131027-20131030
• [Presentation] 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)
  • Author(s): Maemondo M, Sugawara S, Harada T, Fukumoto S, Inoue A, Ishimoto O, Matsubara N, Harada M, Kobayashi K, Nukiwa T
  • Organizer: The European Cancer Congress 2013
  • Place of Presentation: Amsterdam
  • Year and Date: 20130927-20131001
• [Presentation] 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)
  • Author(s): 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
  • Organizer: 49th ASCO Annual Meeting
  • Place of Presentation: CHICAGO
  • Year and Date: 20130531-20130604
• [Presentation] 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)
  • Author(s): 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
  • Organizer: 49th ASCO Annual Meeting
  • Place of Presentation: CHICAGO
  • Year and Date: 20130531-20130604
• [Book] 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)
  • Author(s): 前門戸任
  • Total Pages: p196-200
  • Publisher: MEDICAL VIEW社
• [Book] Medical Practice M.P, vol.30/No.7 One Point Advice, Do not harm (2013)
  • Author(s): 前門戸任
  • Total Pages: p1268
  • Publisher: 文光堂