Comprehensive gene analysis of imatinib resistance and development of new drugs for treatment in GIST

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K18154
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kumamoto University
• Principal Investigator: KOGA Yuki 熊本大学, 病院, 非常勤診療医師 (40835170)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: GIST / 薬剤耐性 / FBXW7

Outline of Final Research Achievements

Gastrointestinal stromal tumor (GIST) has highly resistant to chemotherapy and radiation therapy in unresectable or recurrent cases, therefore those cases have a poor prognosis. The purpose of this study is to elucidate the mechanism of resistance to the therapeutic drug imatinib (tyrosine kinase inhibitor).
Gene analysis in two cell lines, normal GIST cell line and the established imatinib-resistant cell line, showed that several genes may be associated with imatinib resistance. Focusing on the cell cycle regulator FBXW7 (tumor suppressor gene), immunostaining of clinical samples showed that FBXW7 is involved in the prognosis and malignancy of GIST. In addition, there was a difference in prognosis between the presence or absence of postoperative adjuvant treatment with imatinib and the expression of FBXW7, suggesting the involvement of imatinib resistance and FBXW7.

Free Research Field

GISTとがん抑制遺伝子であるFBXW7の関係を中心にGISTの悪性度、薬剤耐性など

Academic Significance and Societal Importance of the Research Achievements

本研究は消化管間質腫瘍（GIST）の悪性度、薬剤耐性に関与する研究を行いました。癌の細胞増殖を抑えるがん抑制遺伝子であるFBXW7がGISTの予後不良因子であることを免疫染色で示した。またイマチニブによる補助治療の有無でFBXW7の発現と予後が変化していた。以上のことからFBXW7遺伝子はGISTの予後に関連し、薬剤耐性にも関与する可能性が考えられた。今後治療の効果予測や、新規の治療ターゲットとして期待できる。