2011 Fiscal Year Final Research Report
Molecular-based approach for overcoming acquired resistance to EGFR tyrosine kinase inhibitors
| Project/Area Number |
21591011
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | Kinki University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
NAKAGAWA Kazuhiko 近畿大学, 医学部, 教授 (40298964)
NISHIO Kazuto 近畿大学, 医学部, 教授 (10208134)
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| Project Period (FY) |
2009 – 2011
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| Keywords | 非閉塞性肺疾患 / 肺線維症 / 呼吸器感染症 / 癌 |
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| Research Abstract |
Most non-small cell lung cancer(NSCLC) tumors with activatingmutations of the EGFR are initially responsive to EGFR tyrosine kinase inhibitors(TKIs), but they subsequently develop resistance to these drugs. The effects of the second-generation, irreversible EGFR-TKI BIBW2992 and the TS-targeting agents S-1(or 5-fluorouracil) or pemetrexed synergistically inhibited the proliferation of NSCLC cells with the T790Mmutation in vitro. BIBW2992 induced down-regulation of TS in the gefitinib-resistant NSCLC cells, implicating depletion of TS in the enhanced antitumor effect of the combination therapy. The combination of BIBW2992 and either the oral fluoropyrimidine S-1 or pemetrexed also inhibited the growth of NSCLC xenografts with the T790Mmutation to an extent greater than that apparent with either agent alone. The addition of TS-targeting drugs to BIBW2992 is a promising strategy to overcome EGFR-TKI resistance inNSCLC with the T790Mmutation of EGFR.
Loss of PTEN(phosphatase and tensin homolog) was recently shown to contribute to resistance to EGFR-TKIs in EGFRmutation. positiveNSCLC through activation of the protein kinaseAKT. The combination therapywithYM155 and erlotinib inhibited the growth of tumors formed by EGFRmutation. positive, PTEN-deficientNSCLC cells in nudemice to a greater extent than did treatment with either drug alone. These results thus indicate that persistent activation of signaling by the AKT-survivin pathway induced by PTENloss underlies a mechanismof resistance to erlotinib-induced apoptosis in EGFRmutation. positiveNSCLC. They further suggest that the targeting of survivin has the potential to overcome EGFR-TKI resistance in EGFRmutation-positiveNSCLC.
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Research Products
(50 results)
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[Journal Article] Combined effect of ALK and MEK inhibitor in EML4-ALK-positive non-small-cell lung cancer cells2012
Author(s)
Tanizaki J, Okamoto I, Takezawa K, Sakai K, Azuma K, Kuwata K, Yamaguchi H, Hatashita E, Nishio K, Janne PA, Nakagawa K
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Journal Title
British Journal of Cancer
Volume: 106
Pages: 763-767
Peer Reviewed
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[Journal Article] Phase I clinical study of the angiogenesis inhibitor TSU-68 combined with carboplatin and paclitaxel in chemotherapy-naive patients with advanced non-small cell lung cancer2012
Author(s)
Okamoto I, Yoshioka H, Takeda K, Satouchi M, Yamamoto N, Seto T, Kasahara K, Miyazaki M, Kitamura R, Ohyama A, Hokoda N, Nakayama H, Yoshihara E, Nakagawa K
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Journal Title
Journal of Thoracic Oncology
Volume: 7
Pages: 427-433
Peer Reviewed
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[Journal Article] Feasibility study of two schedules of sunitinib in combination with pemetrexed in patients with advanced solid tumors2012
Author(s)
Okamoto I, Shimizu T, Miyazaki M, Tsurutani J, Ichikawa Y, Terashima M, Takeda M, Fumita S, Ohki E, Kimura N, Hashimoto J, Nakagawa K
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Journal Title
Investigational New Drugs
Volume: 30
Pages: 639-646
Peer Reviewed
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[Journal Article] Association of the expression of mutant EGFR protein as determined with mutation-specific antibodies in non-small cell lung cancer with progression-free survival after gefitinib treatment2012
Author(s)
Azuma K, Okamoto I, Kawahara A, Taira T, Nakashima K, Hattori S, KinoshitaT, Takeda M, Nakagawa K, Takamori S, Kuwano M, Ono M, KageM
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Journal Title
Journal of Thoracic Oncology
Volume: 7
Pages: 122-127
Peer Reviewed
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[Journal Article] Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab2011
Author(s)
Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, Ercan D, Rogers A, Roncalli M, Takeda M, FujisakaY, Philips J, Shimizu T, Maenishi O, Cho Y, Sun J, Destro A, Taira K, Takeda K, OkabeT, Swanson J, Itoh H, Takada M, Lifshits E, Okuno K, Engelman A J, Shivdasani A R, Nishio K, Fukuoka M, Garcia V M, Nakagawa K, and Janne A. P
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Journal Title
Science Translation Medicine
Volume: 3
Pages: 99ra86
Peer Reviewed
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[Journal Article] Randomized, open-label, phase III, noninferiority trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-naive patients with advanced non-small cell lung cancer : results of a West Japan Oncology Group(LETS) study2010
Author(s)
Okamoto I, Yoshioka H, Morita S, Ando M, Takeda K, Seto T, Yamamoto N, Saka H, Asami K, Hirashima T, Kudoh S, Satouchi M, Ikeda N, Iwamoto Y, Sawa T, Miyazaki M, Tamura K, Kurata K, Fukuoka M, Nakagawa K
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Journal Title
Journal of Clinical Oncology
Volume: 28(36)
Pages: 5240-5246
Peer Reviewed
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[Journal Article] Phase I Safety, Pharmacokinetic, and Biomarker Study of BIBF 1120, an Oral Triple Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors2010
Author(s)
Okamoto I, Kaneda H, Satoh T, Okamoto W, Miyazaki M, Morinaga R, Ueda S, Terashima M, Tsuya A, Sarashina A, Konishi K, Arao T, Nishio K, Kaiser R, Nakagawa K
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Journal Title
Molecular Cancer Therapeutics
Volume: 9(10)
Pages: 2825-2833
Peer Reviewed
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[Journal Article] Does escalation study of pemetrexed in combination with carboplatin followed by pemetrexed maintenance therapy for advanced non-small cell lung cancer2010
Author(s)
Okamoto I, Takeda K, Daga H, Miyazaki M, Yonesaka K, Kiyota H, Tsurutani J, Ueda S, Ichikawa Y, Takeda M, Sekiguchi R, Tominaga K, Enatsu S, Nambu Y, Nakagawa K
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Journal Title
Lung Cancer
Volume: 70(2)
Pages: 168-173
Peer Reviewed
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[Journal Article] Phase I clinical and pharmacokinetic study of sorafenib in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer2010
Author(s)
Okamoto I, Miyazaki M, Morinaga R, Kaneda H, Ueda S, Hasegawa Y, Satoh T, Kawada A, Fukuoka M, Fukino K, Tanigawa T, Nakagawa K
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Journal Title
Investigational New Drugs
Volume: 28(6)
Pages: 844-853
Peer Reviewed
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[Journal Article] Disturbance of the Growth Hormone-Insulin-like Growth Factor-1 Axis Associated with Poor Performance Status in Patients with Solid Tumors2010
Author(s)
Okamoto I, Munakata M, Miyazaki M, Satoh T, Takahata T, Takamatsu Y, Muto O, Koike K, Ishitani K, Mukaiyama T, Sakata Y, Nakagawa K, Tamura K
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Journal Title
Japanese Journal of Clinical Oncology
Volume: 40(3)
Pages: 222-226
Peer Reviewed
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[Journal Article] TAK-701, a humanized monoclonal antibody to HGF, reverses gefitinib resistance induced by tumor-derived HGF in non-small cell lung cancer with an EGFR mutation2010
Author(s)
Okamoto W, Okamoto I, Tanaka K, Hatashita E, Yamada Y, Kuwata K, Yamaguchi H, Arao T, Nishio K, Fukuoka M, Janne PA, Nakagawa K
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Journal Title
Molecular Cancer Therapeutics
Volume: 9(10)
Pages: 2785-2792
Peer Reviewed
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[Journal Article] Identification of c-Src as a potential therapeutic target for gastric cancer and of MET activation as a cause of resistance to c-Src inhibition2010
Author(s)
Okamoto W, Okamoto I, Yoshida T, Okamoto K, Takezawa K, Hatashita E, Yamada Y, Kuwata K, Arao T, Yanagihara K, Fukuoka M, Nishio K, Nakagawa K
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Journal Title
Molecular Cancer Therapeutics
Volume: 9(5)
Pages: 1188-1197
Peer Reviewed
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[Journal Article] Marked anti-tumour activity of the combination of YM155, a novel survivin suppressant, and platinum-based drugs2010
Author(s)
Iwasa T, Okamoto I, Takezawa K, Yamanaka K, Nakahara T, Kita A, Koutoku H, Sasamata M, Hatashita E, Yamada Y, Kuwata K, Fukuoka M, Nakagawa K
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Journal Title
British Journal of Cancer
Volume: 103(1)
Pages: 36-42
Peer Reviewed
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