Understanding and overcoming drug resistance to EGFR-inhibitors for lung cancer

• Project/Area Number: 25293302
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Respiratory surgery
• Research Institution: Okayama University
• Principal Investigator: Toyooka Shinichi 岡山大学, 医歯(薬)学総合研究科, 教授 (30397880)
• Co-Investigator(Kenkyū-buntansha): SOH Junichi 岡山大学, 病院, 講師 (90559890) ; MATSUDA Fumihiko 京都大学, 大学院医学研究科, 教授 (50212220) ; YAMAMOTO Hiromasa 岡山大学, 病院, 助教 (40467733) ; TSUKUDA Kazunori 岡山大学, 病院, 講師 (20346430) ; ASANO Hiroaki 岡山大学, 病院, 助教 (70534775) ; MIYOSHI Shinichiro 岡山大学, 大学院医歯薬学総合研究科, 教授 (00190827) ; SHIEN Kazuhiko 岡山大学, 大学院医歯薬学総合研究科, 助教 (30708079)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2015: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: 原発性肺癌 / 薬剤耐性 / 癌幹細胞 / 上皮成長因子受容体チロシンキナーゼ阻害剤 / 上皮間葉移行 / 上皮成長因子受容体チロシンキナーゼ阻害薬

Outline of Final Research Achievements

In this study, we aimed to understand and overcome drug resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) for lung cancer. We established EGFR-TKI resistant lung cancer cell lines, and specified several resistant mechanisms to EGFR-TKI by using these cell lines. Among them, we identified that acquiring of stem-cell like characteristics led to EGFR-TKI resistance, and several novel drugs were still effective to EGFR-TKI resistant cells. It is important to select an appropriate drug to treat acquired EGFR-TKI resistant cells according to each resistant mechanism.

Research Products

• [Journal Article] Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib (2015)
  • Author(s): Shinsuke Hashida, Hiromasa Yamamoto, Kazuhiko Shien, Yuichiro Miyoshi, Tomoaki Ohtsuka, Ken Suzawa, Mototsugu Watanabe, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka
  • Journal Title: Cancer Science Volume: 10 Issue: 10 Pages: 1377-1384
  • DOI: 10.1111/cas.12749
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hsp90 inhibitor NVP-AUY922 enhances the radiation sensitivity of lung cancer cell lines with acquired resistance to EGFR-tyrosine kinase inhibitors. (2015)
  • Author(s): Hashida S, Yamamoto H, Shien K, Ohtsuka T, Suzawa K, Maki Y, Furukawa M, Soh J, Asano H, Tsukuda K, Miyoshi S, Kanazawa S, Toyooka S
  • Journal Title: Oncology Reports Volume: 33 Issue: 3 Pages: 1499-1504
  • DOI: 10.3892/or.2015.3735
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TAE226, a Bis-Anilino Pyrimidine Compound, Inhibits the EGFR-Mutant Kinase Including T790M Mutant to Show Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells (2015)
  • Author(s): Otani H, Yamamoto H, Takaoka M, Sakaguchi M, Soh J, Jida M, Ueno T, Kubo T, Asano H, Tsukuda K, Kiura K, Hatakeyama S, Kawahara E, Naomoto Y, Miyoshi S, Toyooka S
  • Journal Title: PLoS One Volume: 10 Issue: 6 Pages: e0129838-e0129838
  • DOI: 10.1371/journal.pone.0129838
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Docetaxel-resitant non-small cell lung cancer cells that acquired cross-resistance to EGFR-tyrosine kinase inhibitor (2015)
  • Author(s): Haiyang Chen, Ken Suzawa, Shinsuke Hashida, Tomoaki Ohtsuka, Mototsugu Watanabe, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] Anti-tumor effect of a bis-anilino pyrimidine compound TAE226 on EGFR-mutant non-small cell lung cancer cells with or without T790M mutation (2015)
  • Author(s): Hiromasa Yamamoto, Hiroki Otani, Munenori Takaoka, Masakiyo Sakaguchi, Junichi Soh, Masaru Jida, Tsuyoshi Ueno, Takafumi Kubo, Hiroaki Asano, Kazunori Tsukuda, Katsuyuki Kiura, Shinji Hatakeyama, Eiji Kawahara, Yoshio Naomoto, Shinichiro Miyoshi, Shinichi Toyooka
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] TAE226, a bis-anilino pyrimidine compound, shows anti-tumor effect on EGFR-mutant non-small cell lung cancer cells including T790M mutant (2015)
  • Author(s): Hiromasa Yamamoto, Hiroki Otani, Munenori Takaoka, Masakiyo Sakaguchi, Junichi Soh, Masaru Jida, Tsuyoshi Ueno, Takafumi Kubo, Hiroaki Asano, Kazunori Tsukuda, Katsuyuki Kiura, Shinji Hatakeyama, Eiji Kawahara, Yoshio Naomoto, Shinichiro Miyoshi, Shinichi Toyooka
  • Organizer: 16th World Conference on Lung Cancer
  • Place of Presentation: 米国
  • Year and Date: 2015-09-06
  • Int'l Joint Research
• [Presentation] Effect of Hsp90 inhibitor NVP-AUY922 with radiation on lung adenocarcinoma cell lines with acquired resistance to EGFR-tyrosine kinase inhibitors (2015)
  • Author(s): Yuho Maki, Shinsuke Hashida, Hiromasa Yamamoto, Kazuhiko Shien, Tomoaki Ohtsuka, Ken Suzawa, Masashi Furukawa, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Susumu Kanazawa, Shinichi Toyooka
  • Organizer: AACR 106th Annual Meeting
  • Place of Presentation: 米国
  • Year and Date: 2015-04-18
  • Int'l Joint Research
• [Presentation] The molecular characters of acquired resistant non－small cell lung cancer cells to afatinib (2014)
  • Author(s): Shinsuke Hashida, Shinichi Toyooka, Tomoaki Ohtsuka, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyosh
  • Organizer: AACR Annual Meeting 2014
  • Place of Presentation: San Diego, California, U.S.A
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] The molecular characters of acquired resistant non-small cell lung cancer cells to afatinib (2014)
  • Author(s): Shinsuke Hashida, Shinichi Toyooka, Tomoaki Ohtsuka, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda,Shinichiro Miyoshi
  • Organizer: AACR Annual Meeting 2014
  • Place of Presentation: San Diego, California, U.S.A