EGFRチロシンキナーゼ阻害剤獲得耐性の分子メカニズムに基づいた耐性克服研究

2011 Fiscal Year Annual Research Report

• Project/Area Number: 21591011
• Research Institution: Kinki University
• Principal Investigator: 岡本 勇 近畿大学, 医学部, 准教授 (10411597)
• Co-Investigator(Kenkyū-buntansha): 中川 和彦 近畿大学, 医学部, 教授 (40298964) ; 西尾 和人 近畿大学, 医学部, 教授 (10208134)
• Keywords: 非閉塞性肺疾患 / 肺線維症 / 呼吸器感染症 / 癌

Research Abstract

1)ゲフィチニブ獲得耐性株における可逆性及び不可逆性EGFRチロシンキナーゼ阻害剤と化学療法の併用療法の検討
上皮成長因子受容体(EGFR)チロシンキナーゼ阻害剤(EGFR-TKIs)はEGFR遺伝子変異陽性非小細胞肺癌患者に顕著な抗腫瘍効果を呈するが、ほぼ全例において耐性を獲得しその治療効果が維持出来なくなる。獲得耐性の分子メカニズムとしてEGFR遺伝子の2次変異(T790M変異)の出現が報告され治療戦略開発が急務となっている。T790M変異EGFRにも不可逆的に結合しEGFRチロシンキナーゼ活性を抑制する第2世代EGFR-TKIsであるBIBW2992はT790MEGFR-TKIs耐性肺癌細胞株において転写因子であるE2F-1を介してTSの発現を抑制した。さらにこれらの耐性肺癌細胞を用いた実験によりBIBW2992とTSを標的とする抗癌剤(S-1あるいはペメトレキセド)との併用は相乗的に抗腫瘍効果を発揮することを見出すことが出来た。
2)PTEN欠失を伴うEGFR遺伝子変異陽性株のゲフィチニブに対する耐性メカニズムとサバイビンとの関連性の検討
EGFR-TKIsに対する耐性のメカニズムの1つとしてPTEN欠失が報告されている。PTEN欠失を伴うEGFR遺伝子変異細胞株ではゲフィチニブを用いてEGFRシグナルを抑制してもPI3K/AKT経路が恒常的に活性化しているためサバイビンの発現低下が生じない。この事象はサバイビンの発現変化がゲフィチニブの感受性に関与することを示唆している。我々はサバイビンに特異的なsiRNAを用い、サバイビンの発現量を低下させることでPTEN欠失耐性株の感受性を回復させることに成功し、すでに臨床第I相試験が終了しているサバイビン抑制剤のYM155とEGFR-TKIsの併用療法が、PTEN欠失による耐性克服に有用であることを示した。

Research Products

• [Journal Article] Combined effect of ALK and MEK inhibitor in EML4-ALK-positive non-small-cell lung cancer cells (2012)
  • Author(s): Tanizaki J, Okamoto I, Takezawa K, Sakai K, Azuma K, Kuwata K, Yamaguchi H, Hatashita E, Nishio K, Janne PA, Nakagawa K
  • Journal Title: British Journal of Cancer Volume: 106 Pages: 763-767
  • Peer Reviewed
• [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 cancer (2012)
  • 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
  • Journal Title: Journal of Thoracic Oncology Volume: 7 Pages: 427-433
  • Peer Reviewed
• [Journal Article] Feasibility study of two schedules of sunitinib in combination with pemetrexed in patients with advanced solid tumors (2012)
  • 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
  • Journal Title: Investigational New Drugs Volume: 30 Pages: 639-646
  • Peer Reviewed
• [Journal Article] Phamacokinetics of docetaxel in a patient with non-small cell lung cancer undergoing continuous ambulatory peritoneal dialysis (2012)
  • Author(s): Kaneda H
  • Journal Title: Journal of Thoracic Oncology Volume: 7 Pages: 621-622
  • Peer Reviewed
• [Journal Article] Successful long-term treatment with pemetrexed of NSCLC associated with EML4-ALK and low thymidylate synthase expression (2012)
  • Author(s): Takeda M
  • Journal Title: Clinical Lung Cancer Volume: 13 Pages: 157-159
  • Peer Reviewed
• [Journal Article] Overcoming Erlotinib Resistance in EGFR Mutation-Positive Non-Small Cell Lung Cancer Cells by Targeting Survivin (2012)
  • Author(s): Okamoto K
  • Journal Title: Molecular Cancer Therapeutics Volume: 11 Pages: 204-213
  • Peer Reviewed
• [Journal Article] Roles of BIM induction and survivin down-regulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification (2011)
  • Author(s): Tanizaki J, Okamoto I, Fumita S, Okamoto W, Nishio K, Nakagawa K
  • Journal Title: Oncogene Volume: 30 Pages: 4097-4106
  • Peer Reviewed
• [Journal Article] Thymidylate synthase and dihydropyrimidine dehydrogenase expression levels are associated with response to S-1 plus carboplatin in advanced non-small cell lung cancer (2011)
  • Author(s): Takeda M, Okamoto I, Hirabayashi N, Kitano M, Nakagawa K
  • Journal Title: Lung Cancer Volume: 73(1) Pages: 103-109
  • Peer Reviewed
• [Journal Article] MET Tyrosine Kinase Inhibitor Crizotinib (PF-02341066) Shows Differential Antitumor Effects in Non-small Cell Lung Cancer According (2011)
  • Author(s): Tanizaki J
  • Journal Title: Journal of Thoracic Oncology Volume: 10 Pages: 1624-1631
  • Peer Reviewed
• [Journal Article] Differential roles of trans-phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET (2011)
  • Author(s): Tanizaki J
  • Journal Title: British Journal of Cancer Volume: 105 Pages: 807-813
  • Peer Reviewed
• [Journal Article] Single-agent gefitinib with concurrent radiotherapy for locally advanced non-small cell lung cancer harboring mutations of the epidermal growth (2011)
  • Author(s): Okamoto I
  • Journal Title: Lung Cancer Volume: 72(1) Pages: 199-204
  • Peer Reviewed
• [Journal Article] Tymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer (2011)
  • Author(s): Takezawa K
  • Journal Title: British Journal of Cancer Volume: 104(10) Pages: 1594-1601
  • Peer Reviewed
• [Journal Article] Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer (2011)
  • Author(s): Takezawa K
  • Journal Title: Clinical Cancer Research Volume: 17(8) Pages: 2140-2148
  • Peer Reviewed
• [Journal Article] Differential roles of STAT3 depending on the mechanism of STAT3 activation in gastric cancer cells (2011)
  • Author(s): Okamoto W
  • Journal Title: British Journal of Cancer Volume: 105(3) Pages: 407-412
  • Peer Reviewed
• [Presentation] Emerging role of pemetrexed for first-line and maintenance chemotherapy for advanced nonsquamous NSCLC (2011)
  • Author(s): 岡本勇
  • Organizer: 第52回日本肺癌学会総会
  • Place of Presentation: 大阪国際会議場(大阪府)
  • Year and Date: 2011-11-03
• [Presentation] Molecular Based Patient Selection in Global Clinical Trials for Non-Small Cell Lung Cancer (2011)
  • Author(s): Okamoto I
  • Organizer: The European Multidisciplinary Cancer CongressESMO/JSMO Joint Symposium
  • Place of Presentation: ストックホルム(スウェーデン)
  • Year and Date: 2011-09-26
• [Presentation] Controversies in the Treatment for Advanced Cancer Controversies in the maintenance therapy for metastatic NSCLC (2011)
  • Author(s): Okamoto I
  • Organizer: 第9回日本臨床腫瘍学会学術集会ASCO/JSMO Joint Symposium
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2011-07-21
• [Presentation] 化学放射線療法の新展開放射線療法における分子標的治療薬の役割と展望 (2011)
  • Author(s): 岡本勇
  • Organizer: 第9回日本臨床腫瘍学会学術集会日本臨床腫瘍学会・日本放射線腫瘍学会合同シンポジウム
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2011-07-21
• [Presentation] 肺癌治療のControversy非小細胞肺癌治療におけるEGFRチロシンキナーゼ阻害剤(EGFR-TKIs)の諸問題 (2011)
  • Author(s): 岡本勇
  • Organizer: 第9回日本臨床腫瘍学会学術集会ワークショップ
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2011-07-21
• [Presentation] 化学療法総論II:分子標的薬剤の種類 (2011)
  • Author(s): 岡本勇
  • Organizer: 第9回日本臨床腫瘍学会第18回教育セミナーBセッション
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2011-07-21
• [Presentation] Phase III trial comparing carboplatin/S-1 to carboplatin/paclitaxel in treatment-naive patients with advanced non-small cell lung cancer (NSCLC) : sugbroup analysis and updated results of the LETS study (2011)
  • Author(s): Satouchi M
  • Organizer: 14th World Conference on Lung Cancer
  • Place of Presentation: アムステルダム(オランダ)
  • Year and Date: 2011-07-05
• [Presentation] Phase III study comparing the effects of carboplatin plus S-1 and carboplatin plus paclitaxel in chemotherapy-naive patients with advanced non-small cell lung cancer : An updated report of the LETS study (WJTOG3605) (2011)
  • Author(s): Hirashima T
  • Organizer: 47th American Society of Clinical Oncology Annual Meeting
  • Place of Presentation: シカゴ(アメリカ)
  • Year and Date: 2011-06-06
• [Presentation] Survival results of a randomized, phase III trial of nab-paclitaxel and carboplatin compared with cremophor based paclitaxel and carboplatin as first-line therapy in advanced non-small cell lung cancer (2011)
  • Author(s): Socinski A.M.
  • Organizer: 47th American Society of Clinical Oncology Annual Meeting
  • Place of Presentation: シカゴ(アメリカ)
  • Year and Date: 2011-06-04
• [Presentation] A phase II trial of afatinib (BIBW 2992) in patients (pts) with advanced non-small cell lung cancer previously treated with erlotinib (E) or gefitinib (G) (2011)
  • Author(s): Yamamoto N
  • Organizer: 47th American Society of Clinical Oncology Annual Meeting
  • Place of Presentation: シカゴ(アメリカ)
  • Year and Date: 2011-06-03