Development of novel targeted therapy for lung cancer with activating Ras mutation

• Project/Area Number: 23790903
• 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: TAKEUCHI Shinji 金沢大学, がん進展制御研究所, 助教 (90565384)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 肺がん / Ras / ROS / 肺癌 / 活性酸素

Research Abstract

There are still no effective targeted therapies for patients with K-ras activating mutations which is a cause of intrinsic resistance to EGFR-TKI. Here, we assessed therapeutic effect of β-phenylthyl isothiocynate (PEITC) on lung cancer cellswith K-ras activating mutations through production of reactive oxygen species (ROS).Treatment with PEITC reduced cell viability and induced apoptosis in K-ras mutant lung cancer cells. In a xenograft model, PEITC dramatically reduced tumor growth with less toxicity. Moreover, normal human fibloblasts and K-ras wild lung cancer cells weresignificantly less sensitive to PEITC. Our findings suggest that PEITC can selectively kill lung cancer cells with K-ras activating mutations.

Research Products

• [Journal Article] The novel phosphoinositide 3-kinase-mammalian target of rapamycin inhibitor, BEZ235, circumvents erlotinib resistance of epidermal growth factor receptor mutant lung cancer cells triggered by hepatocyte growth factor. (2013)
  • Author(s): Sano T, Yano S, et al.
  • Journal Title: Int J Cancer Volume: 133 Issue: 2 Pages: 505-13
  • DOI: 10.1002/ijc.28034
  • 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] 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] 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] 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] 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] 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] Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR activating and gatekeeper mutations. (2012)
  • Author(s): Yamada T, Takeuchi S, et al.
  • Journal Title: Oncogene. Volume: Epub ahead of print
  • NAID: 120004997024
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor induces resistance to anti-epidermal growth factor receptor antibody in lung cancer. (2012)
  • Author(s): Yamada T, et al..
  • Journal Title: J Thorac Oncol Volume: 7 Pages: 272-280
  • 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
• [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] 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] 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
• [Presentation] 分子標的薬に対する側副経路活性化による耐性メカニズム (2012)
  • Author(s): 竹内伸司, 矢野聖二
  • Organizer: 日本がん分子標的治療学会第16回学術集会
  • Year and Date: 2012-06-28
• [Presentation] 分子標的薬に対する側副経路活性化による耐性メカニズム (2012)
  • Author(s): 竹内伸司
  • Organizer: 日本がん分子標的治療学会第16回学術集会
  • Place of Presentation: 北九州市 西日本総合展示場
• [Presentation] Met/VEGFR-2阻害剤E7050は変異型EGFR肺がんにおいてHGFによるEGFR-TKI耐性誘導を克服する (2011)
  • Author(s): 竹内 伸司, Wang Wei, Li Qi, 山田 忠明, Donev Ivan, 小泉 瞳, 中村 隆弘, 松本 邦夫, 西岡 安彦, 曽根 三郎, 上仲 俊光, 矢野 聖二
  • Organizer: 第70回日本がん学会学術総会
  • Year and Date: 2011-10-03
• [Presentation] Dual Inhibition of Met Kinase and Angiogenesis to Overcome HGF-induced EGFR-TKI Resistance in EGFR Mutant Lung Cancer (2011)
  • Author(s): 竹内 伸司
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県)
• [Book] Biotherapy 25巻5号 (2011)
  • Author(s): 竹内伸司, 矢野聖二
  • Publisher: がんと化学療法社
• [Remarks]
  • URL: http://syuyounaika.w3.kanazawa-u.ac.jp/