Combining Afatinib and Cetuximab synergistically increases their cytotoxicity for EGFR T790M-harboring cells
Project/Area Number |
24591184
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Respiratory organ internal medicine
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Research Institution | Miyagi 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.
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Report
(4 results)
Research Products
(29 results)
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[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.
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Journal Title
Biochem Biophy Res Commun
Volume: 455
Issue: 3-4
Pages: 269-276
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[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.
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Journal Title
Lancet Oncol.
Volume: 15
Issue: 11
Pages: 1236-1244
DOI
Related Report
Peer Reviewed
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[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.
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Journal Title
J Pathol
Volume: 234
Issue: 2
Pages: 277-288
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[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;
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Journal Title
Lung Cancer
Volume: 86
Issue: 2
Pages: 195-200
DOI
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
Respir Investig.
Volume: 52
Issue: 3
Pages: 190-194
DOI
Related Report
Peer Reviewed
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[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
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Journal Title
Oncologist
Volume: 19
Issue: 4
Pages: 352-353
DOI
Related Report
Peer Reviewed
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[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
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Journal Title
Lung Cancer
Volume: vol.82
Issue: 1
Pages: 109-114
DOI
Related Report
Peer Reviewed
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[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
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Journal Title
Cancer Sci
Volume: 103
Issue: 4
Pages: 760-766
DOI
Related Report
Peer Reviewed
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[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.
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Journal Title
Oncologist
Volume: 17
Issue: 6
Pages: 863-70
DOI
Related Report
Peer Reviewed
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[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
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Journal Title
Clin Cancer Res
Volume: 18
Issue: 20
Pages: 5682-5689
DOI
Related Report
Peer Reviewed
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[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
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[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
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[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
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[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
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[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
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[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
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[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
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[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
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[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
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[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
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[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
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