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Combining Afatinib and Cetuximab synergistically increases their cytotoxicity for EGFR T790M-harboring cells

Research Project

Project/Area Number 24591184
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionMiyagi Prefectural Hospital Organization Miyagi Cancer Center

Principal Investigator

MAEMODNO MAKOTO  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) TANAKA Nobuyuki  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)
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords癌 / 非小細胞肺癌 / 治療法 / 肺癌 / EGFR-TKI / EGFR
Outline of Final Research Achievements

TKIs are effective for NSCLC patients with EGFR-activating mutations. However, these patients eventually develop resistance, most frequently by T790M mutation. Combining a second-generation TKI with an anti-EGFR monoclonal antibody has been shown to improve clinical outcomes, although the mechanism remains elusive. To investigate this mechanism, we used EGFR-negative K562 cells. Double-mutant EGFRs were moderately sensitive to afatinib, but minimally affected by cetuximab. Combining afatinib and cetuximab synergistically increased cytotoxity for K562 cells carrying double-mutant EGFRs. Apoptosis in these cells was preceded by induction of BIM and activation of Caspase-3 and PARP. Afatinib induced EGFR recycling to the cell surface, leading to the cetuximab-mediated recognition and subsequent degradation. These results suggest that the synergistic effect exerted by afatinib and cetuximab against NSCLCs has a potential in the future clinical application.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (29 results)

All 2014 2013 2012

All Journal Article (13 results) (of which Peer Reviewed: 13 results,  Acknowledgement Compliant: 2 results,  Open Access: 1 results) Presentation (14 results) Book (2 results)

  • [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., Tanaka, N.
    • Journal Title

      Biochem Biophy Res Commun

      Volume: 455 Issue: 3-4 Pages: 269-276

    • DOI

      10.1016/j.bbrc.2014.11.003

    • Related Report
      2014 Annual Research Report
    • 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 Issue: 11 Pages: 1236-1244

    • DOI

      10.1016/s1470-2045(14)70381-x

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] An activation of LC3A-mediated autophagy contributes to de novo and acquired resistance to EGFR tyrosine kinase inhibitors in lung adenocarcinoma2014

    • 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 Issue: 2 Pages: 277-288

    • DOI

      10.1002/path.4354

    • Related Report
      2014 Annual Research Report
    • 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 Issue: 2 Pages: 195-200

    • DOI

      10.1016/j.lungcan.2014.08.019

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phase II study of amrubicin combined with carboplatin for refractory relapsed small-cell lung cancer: North Japan Lung Cancer Group Trial 08022014

    • 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 Issue: 3 Pages: 190-194

    • DOI

      10.1016/j.resinv.2013.12.005

    • Related Report
      2014 Annual Research Report
    • 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 08012014

    • 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 Issue: 4 Pages: 352-353

    • DOI

      10.1634/theoncologist.2013-0411

    • Related Report
      2014 Annual Research Report 2013 Research-status Report
    • 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 Issue: 1 Pages: 109-114

    • DOI

      10.1016/j.lungcan.2013.07.003

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cigarette smoking and lung cancer risk according to histological type in Japanese men and women.2013

    • Author(s)
      Seki T, Takahashi S, et al.
    • Journal Title

      Cancer Sci

      Volume: 104 Issue: 11 Pages: 1515-1522

    • DOI

      10.1111/cas.12273

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] 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

    • Author(s)
      Inoue A, Kobayashi K, Maemondo M, et al
    • Journal Title

      Ann Oncol

      Volume: 24 Issue: 1 Pages: 54-9

    • DOI

      10.1093/annonc/mds214

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma2012

    • Author(s)
      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
    • Journal Title

      Cancer Sci

      Volume: 103 Issue: 4 Pages: 760-766

    • DOI

      10.1111/j.1349-7006.2012.02216.x

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] 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 Trial2012

    • Author(s)
      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.
    • Journal Title

      Oncologist

      Volume: 17 Issue: 6 Pages: 863-70

    • DOI

      10.1634/theoncologist.2011-0426

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article]2012

    • Author(s)
      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
    • Journal Title

      Clin Cancer Res

      Volume: 18 Issue: 20 Pages: 5682-5689

    • DOI

      10.1158/1078-0432.ccr-11-2947

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Runx1-deficiency in CD4+ T Cells Causes Fatal Autoimmune Inflammatory Lung Disease due to Spontaneous Hyperactivation of Cells2012

    • Author(s)
      Wong WF
    • Journal Title

      J. Immunol.

      Volume: 188 Issue: 10 Pages: 5408-5420

    • DOI

      10.1038/bjc.2012.422

    • Related Report
      2012 Research-status Report
    • 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
    • Related Report
      2014 Annual Research Report
  • [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 trial2014

    • 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
    • Related Report
      2014 Annual Research Report
  • [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
    • Related Report
      2014 Annual Research Report
  • [Presentation] Randomized phase 2 study of carboplatin plus irinotecan (CI) versus carboplatin plus amrubicin (CA) for extensive disease small-cell lung cancer (ED-SCLC): NJLCG09012014

    • 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
    • Related Report
      2014 Annual Research Report
  • [Presentation] A Case of Small Cell Lung Cancer with Cancer-Associated Retinopathy (CAR) Accompanied by Circulating Anti-CRMP5/CV2 Antibodies2013

    • 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
    • Related Report
      2013 Research-status Report
  • [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
    • Related Report
      2013 Research-status Report
  • [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
    • Related Report
      2013 Research-status Report
  • [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: NJLCG08042013

    • 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
    • Related Report
      2013 Research-status Report
  • [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: NJLCG08042013

    • 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
    • Related Report
      2013 Research-status Report
  • [Presentation] North Japan Lung Cancer Group 08032013

    • 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
    • Related Report
      2013 Research-status Report
  • [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 08032013

    • 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
    • Related Report
      2013 Research-status Report
  • [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) harboring2013

    • 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
    • Related Report
      2013 Research-status Report
  • [Presentation] 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 history2012

    • Author(s)
      Maemondo M
    • Organizer
      ESMO
    • Place of Presentation
      Australia
    • Related Report
      2012 Research-status Report
  • [Presentation] 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

    • Author(s)
      Maemondo M
    • Organizer
      ESMO
    • Place of Presentation
      Australia
    • Related Report
      2012 Research-status Report
  • [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
    • Publisher
      MEDICAL VIEW社
    • Related Report
      2013 Research-status Report
  • [Book] Medical Practice M.P, vol.30/No.7 One Point Advice, Do not harm2013

    • Author(s)
      前門戸任
    • Total Pages
      268
    • Publisher
      文光堂
    • Related Report
      2013 Research-status Report

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Published: 2013-05-31   Modified: 2019-07-29  

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