Effects of molecular-targeted drugs on nonsmoking-related lung cancer models

• Project/Area Number: 24591182
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Kawasaki Medical School
• Principal Investigator: TAKIGAWA Nagio 川崎医科大学, 医学部, 教授 (60325107)
• Co-Investigator(Kenkyū-buntansha): KIURA Katsuyuki 岡山大学, 大学病院, 教授 (10243502) ; YAMANE Hiromichi 川崎医科大学, 医学部, 准教授 (50624897) ; TABAYASHI Takayuki 埼玉医科大学, 医学部, 講師 (60624898) ; OCHI Nobuaki 川崎医科大学, 医学部, 講師 (80611615)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: EGFR / mTOR / JAK2 / STAT3 / 肺癌 / 薬剤耐性 / 遺伝子改変マウス / 血管新生

Outline of Final Research Achievements

EGFR mutations are more frequently observed in non-smokers and adenocarcinoma patients. The majority of EGFR mutant lung cancers initially sensitive to EGFR-TKI become resistant to these agents within 1 year. To overcome EGFR-TKI resistance mechanisms, we have studied using EGFR-TKI resistant lung cancer cell lines, xenograft models, and EGFR-transgenic mice. mTOR inhibitor,　JAK2/STAT3 inhibitor, and EGFR/VEGFR dual inhibitor were all effective. Next, second-generation EGFR-TKI, afatinib, was more potent than gefitinib and the combination of afatinib with bevacizumab efficiently suppressed resistant tumors. Furthermore, we established a novel gefitinib-resistant lung cancer cell line and found that gefitinib substantially suppressed the EGFR signaling pathway, whereas ERK was reactivated, dual inhibition of EGFR and SRC restored gefitinib sensitivity. In conclusion, our results indicate that the molecular target drugs may be a potent strategy to overcome the EGFR-TKI resistance.

Research Products

• [Journal Article] Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors. (2014)
  • Author(s): Yasugi M, Takigawa N, Ochi N, Ohashi K, Harada D, Ninomiya T, Murakami T, Honda Y, Ichihara E, Tanimoto M, Kiura K.
  • Journal Title: Exp Cell Res. Volume: 326 Issue: 2 Pages: 201-209
  • DOI: 10.1016/j.yexcr.2014.04.012
  • NAID: 120005526613
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The Role of STAT3 in Non-Small Cell Lung Cancer. (2014)
  • Author(s): Harada D, Takigawa N, Kiura K.
  • Journal Title: Cancers Volume: 26 Issue: 2 Pages: 708-722
  • DOI: 10.3390/cancers6020708
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model (2014)
  • Author(s): Murakami Toshi, Takigawa Nagio, Ninomiya Takashi, Ochi Nobuaki, Yasugi Masaaki, Honda Yoshihiro, Kubo Toshio, Ichihara Eiki, Hotta Katsuyuki, Tanimoto Mitsune, Kiura Katsuyuki
  • Journal Title: Lung Cancer Volume: 83 Issue: 1 Pages: 30-36
  • DOI: 10.1016/j.lungcan.2013.10.011
  • NAID: 120005473065
  • Peer Reviewed
• [Journal Article] Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer. (2014)
  • Author(s): Ochi N, Takigawa N, Harada D, Yasugi M, Ichihara E, Hotta K, Tabata M, Tanimoto M, Kiura K.
  • Journal Title: Exp Cell Res. Volume: 322 Issue: 1 Pages: 168-177
  • DOI: 10.1016/j.yexcr.2014.01.007
  • NAID: 120005517858
  • Peer Reviewed
• [Journal Article] Afatinib prolongs survival compared with gefitinib in an epidermal growth factor receptor-driven lung cancer model. (2013)
  • Author(s): Ninomiya T, Takigawa N, Ichihara E, Ochi N, Murakami T, Honda Y, Kubo T, Minami D, Kudo K, Tanimoto M, Kiura K.
  • Journal Title: Mol Cancer Ther. Volume: 12 Issue: 5 Pages: 589-597
  • DOI: 10.1158/1535-7163.mct-12-0885
  • NAID: 120005359109
  • Peer Reviewed
• [Journal Article] Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency. (2013)
  • Author(s): Takeda H, Takigawa N, Ohashi K, Minami D, Kataoka I, Ichihara E, Ochi N, Tanimoto M, Kiura K.
  • Journal Title: Exp Cell Res Volume: 319 Issue: 4 Pages: 417-427
  • DOI: 10.1016/j.yexcr.2012.12.018
  • NAID: 120005359097
  • Peer Reviewed
• [Journal Article] JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation (2012)
  • Author(s): Harada D, Takigawa N, Ochi N, Ninomiya T, Yasugi M, Kubo T, Takeda H, Ichihara E, Ohashi K, Takata S, Tanimoto M, Kiura K
  • Journal Title: Cancer Sci Volume: 103 Issue: 10 Pages: 1795-1802
  • DOI: 10.1111/j.1349-7006.2012.02363.x
  • NAID: 120005311974
  • Peer Reviewed
• [Presentation] Epidermal growth factor receptor signaling conferred acquired crizotinib resistance to a non-small cell lung cancer cell line harboring the SLC34A2-ROS1 fusion gene (2014)
  • Author(s): Kato Y, Ohashi K, Ichihara E, Isozaki H, Kudo K, Minami D, Kubo T, Sato A, Hotta K, Tabata M, Takigawa N, Tanimoto M, Kiura K
  • Organizer: Annual Meeting of the European Society for Medical Oncology
  • Place of Presentation: Spain, Madrid, Feria de Madrid
  • Year and Date: 2014-09-28
• [Presentation] ALK inactivation induced acquired resistance to alectinib in lung cancer harboring EML4-ALK fusion gene (2014)
  • Author(s): Isozaki H, Ichihara E, Yasugi M, Ochi N, Hotta K, Takigawa N, Sendo T, Tanimoto M, Kiura K.
  • Organizer: Annual Meeting of the American Association for Cancer Research
  • Place of Presentation: USA, San Diego, San Diego Convention Center
  • Year and Date: 2014-04-06
• [Presentation] PTEN deficient lung cancer cells are sensitive to the combination of olaparib with cisplatin through suppressing DNA damage signaling (2013)
  • Author(s): Minami Daisuke, Takigawa Nagio, Takeda Hiromasa, Takata Minoru, Ochi Nobuaki , Ichihara Eiki, Hisamoto Akiko, Hotta Katsuyuki, Tanimoto Mitsune, Kiura Katsuyuki
  • Organizer: AACR Annual Meeting 2013
  • Place of Presentation: Washington Convention Center, Washington, DC, USA
• [Presentation] EGFR遺伝子改変マウスに対するJAK1/2阻害剤(AZD1480)の検討 (2012)
  • Author(s): 村上 斗司、 瀧川 奈義夫、他
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市教育文化会館（北海道札幌市）