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

2017 Fiscal Year Final Research Report

• 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
• Keywords: GIST / イマチニブ / 分子標的治療薬耐性

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.

Free Research Field

外科学