Investigation of the mechanism of EGFR-TKI resistance and establishment of new treatment strategy

• Project/Area Number: 25860643
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Kobe University
• Principal Investigator: Tamura Daisuke 神戸大学, 医学部附属病院, 助教 (80646597)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2015: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 薬剤耐性クローン / EGFR-TKI / がん幹細胞 / 老化細胞 / DTPs / 細胞老化 / 国際情報交換 / EMT / 上皮間葉移行 / Gefitinib / 間質性肺炎 / 薬剤耐性

Outline of Final Research Achievements

Pathway-targeted cancer drug therapies can effectively produce dramatic responses. However, these therapies are not curative and the relatively rapid emergence of drug-tolerant persisters (DTPs) substantially limits the overall therapeutic benefit. This study aimed to clarify the varying composition of DTPs in EGFR mutated non-small lung cancer cells and to develop an effective treatment. Using FACS analysis, DTPs could be separated by CD133 expression pattern. CD133 high population expressed higher stem cell related markers and had other stem cell like properties. On the other hand, CD133 low population exhibited higher expression of cellular senescence associated proteins. Wthaferin A eliminated CD133 high cells effectively. In addition, inhibitors of a highly glucose-consuming condition suppressed CD133 low population emergence.

Research Products

• [Presentation] EGFR-TKI耐性クローンに対する糖代謝阻害剤、癌幹細胞治療薬の有効性について (2016)
  • Author(s): 國政啓、永野達也、徳永俊太郎、田村大介、立原素子、小林和幸、西村善博
  • Organizer: 第56回日本呼吸器学会学術講演会
  • Place of Presentation: 京都
  • Year and Date: 2016-04-09
• [Presentation] GFR-TKI耐性クローンに対する糖代謝阻害剤、癌幹細胞治療薬の有効性について (2015)
  • Author(s): 津村成美、永野達也、下野洋平、國政啓、徳永俊太郎、田村大介、立原素子、小林和幸、西村善博
  • Organizer: 第56回日本肺癌学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2015-11-28
• [Presentation] The glucose metabolism targeting therapies and withaferinA eliminate EGFR-TKI induced drug-tolerant persisters in NSCLC cells. (2015)
  • Author(s): 國政啓、永野達也、下野洋平、徳永俊太郎、田村大介、立原素子、小林和幸、西村善博
  • Organizer: AACR 2015
  • Place of Presentation: アメリカ合衆国（フィラデルフィア）
  • Year and Date: 2015-04-19
• [Presentation] The glucose metabolic targeting therapies and withaferin A eliminate epidermal growth factor tyrosine kinase inhibitor-induced drug-tolerant persisters in non-small lung cancer cells (2015)
  • Author(s): Kunimasa K, Nagano T, Shimono Y, Tokunaga S, Tamura D, Tachihara M, Kobayashi K, Nishimura Y
  • Organizer: AACR Annual Meeting 2015
  • Place of Presentation: Philadelphia
  • Year and Date: 2015-04-18
  • Int'l Joint Research