Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations

• Project/Area Number: 23790902
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Kanazawa University
• Principal Investigator: YAMADA Tadaaki 金沢大学, 大学病院, 講師 (00507048)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 肺癌 / 分子標的治療 / EGFR変異 / 足場蛋白質 / 薬剤耐性 / EGFR / がん分子標的 / 上皮成長因子受容体

Research Abstract

We focused on Akt kinase-interacting protein1 (Aki1), a scaffold protein of PI3K /PDK1/Akt, and assessed its role in EGFR mutant lung cancer. Aki1 constitutively associates with mutant EGFR in lung cancer cells. Silencing of Aki1 inhibited cell growth of EGFR mutant lung cancer cells and induced apoptosis of them. Treatment with Aki1 siRNA dramatically inhibited growth of EGFR mutant lung cancer cells in a xenograft model. Moreover, Aki1 was frequently expressed in tumor cells of EGFR mutant lung cancer patients, including those with acquired resistance to EGFR-TKI treatment. Our data suggest that Aki1 may be an ideal target for EGFR mutant lung cancer patients, especially those with acquired EGFR-TKI resistance due to EGFR T790M gatekeeper mutation.

Research Products

• [Journal Article] Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR activating and gatekeeper mutations. (2013)
  • Author(s): Yamada T, Yano S, et al.
  • Journal Title: Oncogene Volume: 32 Issue: 37 Pages: 4427-35
  • DOI: 10.1038/onc.2012.446
  • NAID: 120004997024
  • Peer Reviewed
• [Journal Article] EGFR-TKI resistance due to BIM polymorphism can be circumvented in combination with HDAC inhibition. (2013)
  • Author(s): Nakagawa T, Yano S, et al.
  • Journal Title: Cancer Res Volume: 73 Issue: 8 Pages: 2428-34
  • DOI: 10.1158/0008-5472.can-12-3479
  • Peer Reviewed
• [Journal Article] Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells (2012)
  • Author(s): Yamada, T.
  • Journal Title: Clin. Cancer Res. Volume: 18 Issue: 13 Pages: 3592-3602
  • DOI: 10.1158/1078-0432.ccr-11-2972
  • Peer Reviewed
• [Journal Article] Hsp90 Inhibition Overcomes HGF Triggering Resistance to EGFR-TKIs in EGFR-Mutant Lung Cancer by Decreasing Client Protein Expression and Angiogenesis (2012)
  • Author(s): Koizumi H, Yamada T, Takeuchi S, Nakagawa T, Kita K, Nakamura T, Matsumoto K, Suda K, Mitsudomi T, and Yano S
  • Journal Title: Journal of Thoracic Oncology Volume: Vol. 7: no.7 Issue: 7 Pages: 1078-1085
  • DOI: 10.1097/jto.0b013e3182519a2c
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor induces resistance to anti-epidermal growth factor receptor antibody in lung cancer (2012)
  • Author(s): Yamada T, Takeuchi S, Kita K, Bando H, Nakamura T, Matsumoto K, Yano S
  • Journal Title: J Thorac Oncol Volume: 7 Issue: 2 Pages: 272-80
  • DOI: 10.1097/jto.0b013e3182398e69
  • Peer Reviewed
• [Journal Article] E7050, a Met kinase inhibitor, reverses three different mechanisms of hepatocyte growth factor-induced resistance to tyrosine kinase inhibitors in EGFR mutant lung cancer cells (2012)
  • Author(s): Wang W, Li Q, Takeuchi S, Yamada T, Koizumi H, Nakamura T, Matsumoto K, Mukaida N, Nishioka Y, Sone S, Uenaka T, Yano S
  • Journal Title: Clin Cancer Res Volume: 18 Issue: 6 Pages: 1663-71
  • DOI: 10.1158/1078-0432.ccr-11-1171
  • Peer Reviewed
• [Journal Article] Ligand-triggered resistance to molecular targeted drugs in lung cancer : roles of HGF and EGFR ligands (2012)
  • Author(s): Yano S, Takeuchi S, Nakagawa T, Yamada T
  • Journal Title: Cancer Sci Volume: (In press) Issue: 7 Pages: 1189-1194
  • DOI: 10.1111/j.1349-7006.2012.02279.x
  • Peer Reviewed
• [Journal Article] Dual inhibition of met kinase and angiogenesis to overcome HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer (2012)
  • Author(s): Takeuchi S, Wang W, Li Q, Yamada T, Kita K, Donev IS, Nakamura T, Matsumoto K, Shimizu E, Nishioka Y, Sone S, Nakagawa T, Uenaka T, Yano
  • Journal Title: Am J Pathol Volume: 181 Issue: 3 Pages: 1034-1043
  • DOI: 10.1016/j.ajpath.2012.05.023
  • Peer Reviewed
• [Journal Article] Prognostic Value of Aquired Resistance-related Molecules in Japanese Patients with NSCLC Treated with an EGFR-TKI (2012)
  • Author(s): Uramoto Hidetaka
  • Journal Title: Anticancer Res Volume: 32 Pages: 3785-3790
  • Peer Reviewed
• [Journal Article] Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer (2012)
  • Author(s): Nakagawa T
  • Journal Title: Mol Cancer Ther. Volume: 11 Issue: 10 Pages: 2149-2157
  • DOI: 10.1158/1535-7163.mct-12-0195
  • Peer Reviewed
• [Journal Article] Genetically engineered humanized anti-ganglioside GM2 anti-body against multiple organ metastasis produced by GM2 expressing small cell lung cancer (2011)
  • Author(s): Yamada T, Bando H, Takeuchi S, Kita K, Li Q, Wang W, Akinaga S, Nishioka Y, Sone S, Yano S.
  • Journal Title: Cancer Sci Volume: 102 Issue: 12 Pages: 2157-63
  • DOI: 10.1111/j.1349-7006.2011.02093.x
  • Peer Reviewed
• [Journal Article] The EGFR ligands amphiregulin and heparin-binding EGF-like growth factor promote peritoneal carcinomatosis in CXCR4-expressing gastric cancer (2011)
  • Author(s): Yasumoto K, Yamada T, Kawashima A, Wang W, Li Q, Donev IS, Takeuchi S, Mouri H, Yamashita K, Ohtsubo K, Yano S.
  • Journal Title: Clin Cancer Res Volume: 17 Issue: 11 Pages: 3619-30
  • DOI: 10.1158/1078-0432.ccr-10-2475
  • Peer Reviewed
• [Journal Article] Transient PI3K inhibition induces apoptosis and overcomes HGF-mediated resistance to EGFR-TKIs in EGFR mutant lung cancer (2011)
  • Author(s): Donev IS, Wang W, Yamada T, Li Q, Takeuchi S, Matsumoto K, Yamori T, Nishioka Y, Sone S, Yano S
  • Journal Title: Clin Cancer Res Volume: 17 Issue: 8 Pages: 2260-9
  • DOI: 10.1158/1078-0432.ccr-10-1993
  • Peer Reviewed
• [Journal Article] E7080 suppresses hematogenous multiple organ metastases of lung cancer cells with nonmutated epidermal growth factor receptor (2011)
  • Author(s): Ogino H, Hanibuchi M, Kakiuchi S, Trung Van The, Goto H, Ikuta K, Yamada T, Uehara H, Tsuruoka A, Uenaka T, Wang W, Li Q, Takeuchi S, Yano S, Nishioka Y, Sone S.
  • Journal Title: Mol Cancer Ther Volume: 10 Issue: 7 Pages: 1218-28
  • DOI: 10.1158/1535-7163.mct-10-0707
  • Peer Reviewed
• [Journal Article] Pleural mesothelioma instigates tumor associated fibroblasts to promote prog-ression via malignant cytokine network (2011)
  • Author(s): Li Q, Wang W, Yamada T, Matsumoto K, Bando Y, Uehara H, Nishioka Y, Sone S, Iwakiri S, Itoi K, Utsugi T, Yano S.
  • Journal Title: Am J Pathol Volume: 179 Issue: 3 Pages: 1483-93
  • DOI: 10.1016/j.ajpath.2011.05.060
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor expression in EGFR mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort (2011)
  • Author(s): Yano S, Yamada T, Takeuchi S, Tachibana K, Minami Y, Yatabe Y, Mitsudomi T, Tanaka H, Kimura T, Kudoh S, Nokihara H, Ohe Y, Yokota J, Uramoto U, Yasumoto Y, Kiura K, Higashiyama M, Oda M, Saito H, Yoshida J, Kondoh K, Noguchi M.
  • Journal Title: J Thorac Oncol Volume: 6 Issue: 12 Pages: 2011-7
  • DOI: 10.1097/jto.0b013e31823ab0dd
  • Peer Reviewed
• [Presentation] Paracrine receptor ligands activate bypass tracts and cause ALK inhibitor resistance in EML4-ALK lung cancer cells (2012)
  • Author(s): Yamada T, et al.
  • Organizer: 5th Asia Pacific Lung Cancer Conference(oral presentation)
  • Place of Presentation: ヒルトン福岡シーホーク(福岡県)
  • Year and Date: 2012-11-27
• [Presentation] ALK肺がんのLigandによるALK阻害薬耐性機構とその克服 (2012)
  • Author(s): 山田忠明ら
  • Organizer: 第53回日本肺癌学会総会(ワークショップ)
  • Place of Presentation: 岡山コンベンションセンター(岡山県)
  • Year and Date: 2012-11-08
• [Presentation] EGFR遺伝子変異陽性肺がんにおける新規足場蛋白Aki1の制御 (2012)
  • Author(s): 山田忠明ら
  • Organizer: 第71回日本癌学会総会(一般口演)
  • Place of Presentation: ホテルロイトン札幌(北海道)
  • Year and Date: 2012-09-20
• [Presentation] 非小細胞肺がんにおけるEGFR-TKI耐性 (2012)
  • Author(s): 山田忠明,矢野聖二
  • Organizer: 第10回日本臨床腫瘍学会学術総会(シンポジウム)
  • Place of Presentation: 大阪国際会議場(大阪府)
  • Year and Date: 2012-07-27
• [Presentation] Hsp90 inhibition overcomes HGF-triggering resistance to EGFR-TKIs in EGFR mutant lung cancer by decreasing client protein expression and angiogenesis (2012)
  • Author(s): Yamada T, et al.
  • Organizer: 103thAmerican Association for Cancer Research Annual Meeting (Poster)
  • Place of Presentation: McCormick Place(USA)
  • Year and Date: 2012-04-02
• [Presentation] ALK肺がんのLigandによるALK阻害薬耐性機構とその克服 (2012)
  • Author(s): 山田 忠明
  • Organizer: 第53回日本肺癌学会総会
  • Place of Presentation: 岡山コンベンションセンター（岡山県）
• [Presentation] Paracrine receptor ligands activate bypass tracts and cause ALK inhibitor resistance in EML4-ALK lung cancer cells (2012)
  • Author(s): 山田 忠明
  • Organizer: 5th Asia Pacific Lung Cancer Conference
  • Place of Presentation: ヒルトン福岡シーホーク（福岡県）
• [Presentation] Hepatocyte growth factor induces resistance to anti-epidermal growth factor receptor antibody in lung cancer. (2012)
  • Author(s): Tadaaki Yamada
  • Organizer: 16th JFCR International Symposium on Cancer Chemotherapy
  • Place of Presentation: 日本科学未来館（東京都）
• [Presentation] HGF/MET is a novel therapiutic target for EGFR-TKI resistant lung cancer (2011)
  • Author(s): Yamada T, Yano S
  • Organizer: 第70回日本癌学会総会(International Session)
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-05
• [Presentation] Treatment for EGFR mutant lung cancer (2011)
  • Author(s): 山田忠明,矢野聖二
  • Organizer: 第9回日本臨床腫瘍学会学術総会(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] Hsp90阻害剤は、HGFによるEGFR遺伝子変異陽性肺がんの薬剤耐性を克服する (2011)
  • Author(s): 山田 忠明
  • Organizer: 第11回日本分子生物学会春季シンポジウム
  • Place of Presentation: 石川県立音楽堂（石川県）
• [Presentation] CDDPの心嚢腔内投与が奏効した肺扁平上皮癌による心タンポナーデ合併癌性心膜炎の一剖検例 (2011)
  • Author(s): 山田 忠明
  • Organizer: 第64回肺癌学会北陸支部会
  • Place of Presentation: 福井大学医学部附属病院（福井県）
• [Presentation] Treatment for EGFR mutant lung cancer (2011)
  • Author(s): 山田 忠明
  • Organizer: 第9回日本臨床腫瘍学会学術総会(招待講演)
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] Analysis of tumor immunoreactivity for FGF-2,PDGF-AA, and HGF in malignant pleural mesothelioma patients (2011)
  • Author(s): 山田 忠明
  • Organizer: 第9回日本臨床腫瘍学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] HGF/MET is a novel therapiutic target for EGFR-TKI resistant lung cancer (2011)
  • Author(s): Tadaaki Yamada
  • Organizer: 第70回日本癌学会総会(招待講演)
  • Place of Presentation: 名古屋国際会議場(（愛知県）
• [Presentation] EML4-ALK肺がんにおけるALK阻害薬耐性：EGFRリガンドによる新規耐性機構 (2011)
  • Author(s): 山田 忠明
  • 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）
• [Presentation] Hsp90 inhibition overcomes HGF-triggering resistance to EGFR-TKIs in EGFR mutant lung cancer by decreasing client protein expression and angiogenesis
  • Author(s): 山田 忠明
  • Organizer: 第103回アメリカ癌学会
  • Place of Presentation: McCormick Place（USA）
• [Presentation] HGFによるEGFR変異陽性肺がんの薬剤耐性に対するHsp90阻害薬の治療効果
  • Author(s): 山田 忠明
  • Organizer: 第52回日本呼吸器学会総会
  • Place of Presentation: 神戸コンベンションセンター（兵庫県）
• [Presentation] EML4-ALK肺がんの肝細胞増殖因子による新たなALK阻害薬耐性機構
  • Author(s): 山田 忠明
  • Organizer: 第16回日本がん分子標的治療学会
  • Place of Presentation: 西日本総合展示場（福岡県）
• [Presentation] 非小細胞肺がんにおけるEGFR-TKI耐性
  • Author(s): 山田 忠明
  • Organizer: 第10回日本臨床腫瘍学会学術総会
  • Place of Presentation: 大阪国際会議場（大阪府）
  • Invited
• [Presentation] EGFR遺伝子変異陽性肺がんにおける新規足場蛋白Aki1の制御
  • Author(s): 山田 忠明
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: ホテルロイトン札幌（北海道）
• [Book] 実験医学 (2013)
  • Author(s): 山田忠明,矢野聖二
  • Publisher: 羊土社
• [Book] 日本臨牀 最新肺癌学 (2013)
  • Author(s): 山田 忠明
  • Total Pages: 4
  • Publisher: 日本臨牀社
• [Book] 「Mebio」肺がん治療2012 (2012)
  • Author(s): 山田 忠明
  • Total Pages: 7
  • Publisher: メジカルレビュー社
• [Book] 実験医学 (2012)
  • Author(s): 山田 忠明
  • Total Pages: 6
  • Publisher: 羊土社
• [Book] がん生物学 イラストレイテッド (2011)
  • Author(s): 山田忠明,矢野聖二
  • Publisher: 羊土社
• [Book] がん生物学 イラストレイテッド (2011)
  • Author(s): 山田 忠明
  • Publisher: 羊土社
• [Remarks]
  • URL: http://syuyounaika.w3.kanazawa-u.ac.jp/