The mechanisms for acquired imatinib resistance beyond secondary KIT mutations in gastrointestinal stromal tumor

• Project/Area Number: 15K10098
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Osaka University
• Principal Investigator: Takahashi Tsuyoshi 大阪大学, 医学系研究科, 助教 (50452389)
• Research Collaborator: Yamasaki Makoto 大阪大学, 大学院医学系研究科, 准教授 (50444518) ; Kurokawa Yukinori 大阪大学, 大学院医学系研究科, 助教 (10470197) ; Makino Tomoki 大阪大学, 大学院医学系研究科, 助教 (80528620) ; Miyazaki Yasuhiro 大阪大学, 大学院医学系研究科, 助教 (00571390) ; Tanaka Kouji 大阪大学, 大学院医学系研究科, 助教 (70621019)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: GIST / イマチニブ / 分子標的治療薬耐性 / imatinib / 耐性 / 消化管間質腫瘍 / 分子標的治療 / 薬剤耐性

Outline of Final Research Achievements

The GIST is the most common mesenchymal tumor of the digestive tract, in which proliferation is driven by gain-of-function mutations in KIT. Despite the revolutionary benefits of imatinib, more than 80% of patients eventually develop disease progression driven by secondary resistance mutations in KIT kinase domains. To comprehensively characterize the variants associated with imatinib resistance, we performed a genomic and transcriptomic analysis of four fully resistant cell lines and one partially resistant cell line before acquiring full resistance. We identified single nucleotide variants and copy number alterations by exome sequencing and transcriptional changes from microarrays. The cell line with partial resistance exhibited drastic transcriptional changes despite the few genomic changes. In contrast, fully resistant cell lines had many more genomic changes while the transcriptomic changes were less dramatic.

Research Products

• [Journal Article] Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors. (2017)
  • Author(s): Takahashi T, Elzawahry A, Mimaki S, Furukawa E, Nakatsuka R, Nakamura H, Nishigaki T, Serada S, Naka T, Hirota S, Shibata T, Tsuchihara K, Nishida T, Kato M.
  • Journal Title: Genes Chromosomes Cancer. Volume: 56 Issue: 4 Pages: 303-313
  • DOI: 10.1002/gcc.22438
  • Peer Reviewed / Open Access
• [Journal Article] Clinicopathological characteristics, surgery and survival outcomes of patients with duodenal gastrointestinal stromal tumors. (2016)
  • Author(s): Sugase T, Takahashi T, Nakajima K, Hirota S, Masuzawa T, Nishida T, Kimura Y, Miyazaki Y, Makino T, Kurokawa Y, Yamasaki M, Takiguchi S, Mori M, Doki Y.
  • Journal Title: Digestion. Volume: 94 Issue: 1 Pages: 30-36
  • DOI: 10.1159/000447665
  • Peer Reviewed
• [Presentation] 消化管間葉系肉腫（GIST）に対する分子標的治療耐性メカニズムの検討 (2017)
  • Author(s): 高橋剛、黒川幸典、西田俊朗、廣田誠一、西垣貴彦、和田範子、田中晃司、宮崎安弘、 牧野知紀、山崎誠、中島清一、瀧口修司、森正樹、土岐祐一郎
  • Organizer: 日本癌転移学会
• [Presentation] 消化管間葉系肉腫（GIST）に対する分子標的治療耐性メカニズムの検討 (2016)
  • Author(s): 高橋剛、黒川幸典、西田俊朗、廣田誠一、西垣貴彦、和田範子、田中晃司、宮崎安弘、 牧野知紀、山崎誠、中島清一、瀧口修司、森正樹、土岐祐一郎
  • Organizer: 日本消化器癌発生学会
  • Place of Presentation: 鹿児島
  • Year and Date: 2016-09-15
• [Presentation] 分子標的薬耐性GISTに関わる遺伝子変異の検討 (2015)
  • Author(s): 髙橋 剛
  • Organizer: 日本消化器癌発生学会総会
  • Place of Presentation: 鳥取
  • Year and Date: 2015-11-19